2013 roth and chen oncogene review

7/27/2019 2013 Roth and Chen Oncogene Review

1/12

REVIEW

Sorting out functions of sirtuins in cancerM Roth and WY Chen

The sirtuins (SIRT 17) comprise a family of NAD -dependent protein-modifying enzymes with activities in lysine deacetylation,

adenosinediphospho(ADP)-ribosylation, and/or deacylation. These enzymes are involved in the cells stress response systems and in

regulating gene expression, DNA damage repair, metabolism and survival. Sirtuins have complex roles in both promoting and/or

suppressing tumorigenesis. This review presents recent research progress concerning sirtuins and cancer. On one hand, functional

loss of sirtuin genes, particularly SIRT1, involved in maintaining genome integrity and DNA repair will promote tumorigenesis

because of genomic instability upon their loss. On the other hand, cancer cells tend to require sirtuins for these same processes to

allow them to survive, proliferate, repair the otherwise catastrophic genomic events and evolve. The bifurcated roles of SIRT1, and

perhaps several other sirtuins, in cancer may be in part a result of the nature of the genes that are involved in the cells genome

maintenance systems. The in-depth understanding of sirtuin functions may have significant implication in designing precise

modulation of selective sirtuin members to aid cancer prevention or treatment under defined conditions.

Oncogene advance online publication, 22 April 2013; doi:10.1038/onc.2013.120

Keywords: acquired resistance; cancer; genetic instability; longevity; sirtuin; SIRT1

INTRODUCTION

Sirtuins are mammalian homologs of yeast silent informationregulator 2 (Sir2) encoding a histone deacetylase.1,2 The sevenmammalian members of sirtuins (termed SIRT17) share aconserved catalytic core domain (Figure 1). Despite this homology,sirtuins have divergent enzymatic activities with SIRT13 andSIRT7 primarily as lysine deacetylases, SIRT4 primarily as adeno-sinediphospho (ADP)-ribosyltransferase, SIRT5 as deacetylase anddeacylase, and SIRT6 as ADP-ribosyltransferase and deacetylase.15

In addition, primary localization of these proteins in the cell variessignificantly, reflecting functional distinction of sirtuin members(see Figure 1).

Growing interest in sirtuins largely stems from previous studiesof yeast Sir2 showing that in lower organisms, increased Sir2 genedosage is sufficient to extend lifespan,68 and that Sir2 is at anexus between caloric restriction, resveratrol or other caloricrestriction mimetics and longevity.9,10 More recently, these initialobservations have been scrutinized and refined to show a lack ofan effect ofSir2 in extending lifespan in lower species as well as inmammals.1113 Further adding to the complex nature of the role ofsirtuins in extending lifespan, Kanfi et al.14 described thattransgenic SIRT6 male mice live B1015% longer than theirwild-type littermates. The conflicting literature on the roles of Sir2in longevity contributes in part to the confusion of functions of

mammalian sirtuins, but may also foretell the complexity of thesegenes in mammalian cells.

Research in the past decade has revealed the perplexed andoften controversial roles of sirtuins in promoting versus suppres-sing cancer. Cancer cells alter normal cellular machineries topromote unabated cell proliferation and maximize their lifespan,but as a consequence of their malignant growth, they cut shortthe lifespan of the host organism. Hanahan and Weinberg15 haveelegantly outlined the fundamental mechanisms of cancerpromotion as consisting of sustaining proliferative signaling,

enabling replicative immortality, activating invasion andmetastasis and inducing angiogenesis; meanwhile, as normalcells possess innate mechanisms to antagonize cancer-promotingsignals, the transformed cells must also overcome tumorsuppression mechanisms, namely, by evading growth suppressorsignals and resisting cell death. Crucially underlying thesehallmarks of cancer is the genetic instability of cancer cells.15

Although cancer biologists tend to classify genes into either tumorpromoting or tumor suppressing, only a limited number of genesunambiguously fall into one of these categories, for examples,

MYC as an oncogene and retinoblastoma gene RB as a tumorsuppressor gene.16 Other genes including sirtuins are lessapparent, and the tumor-promoting or -inhibiting propertiesof the genes may depend on the stages of cancer developmentand contextual variables such as tissue of origin, the micro-environment and the exact experimental conditions.15 However,rapid progress has been made most recently in the research onmammalian sirtuins and cancer, which may improve ourunderstanding of these elusive genes and will be highlighted inthis review.

SIRT1

Biochemical overview

SIRT1 shares the greatest homology with yeast Sir2, which wasinitially characterized as an nicotinamide adenine dinucleotide(NAD) -dependent histone deacetylase2 (so-called class IIIhistone deacetylase that is structurally and biochemically distinctfrom class I, II and IV histone deacetylases). SIRT1 deacetylateshistone H4 lysine 16 (H4K16) as well as histone H3 lysine 9 and 14(H3K9 and H3K14, respectively).1 Additionally, SIRT1 deacetylateshistone H1 lysine 26 (H1K26) and is involved in the deposition ofhistone variants.17 These modifications of histone tails are closelyrelated to gene silencing and heterochromatin formation that may

Department of Cancer Biology, Beckman Research Institute, Duarte, CA, USA. Correspondence: Dr WY Chen, Department of Cancer Biology, Beckman Research Institute, City of

Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.

E-mail: [email protected]

Received 4 January 2013; revised 11 February 2013; accepted 18 February 2013

Oncogene (2013), 112

& 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13

www.nature.com/onc
http://dx.doi.org/10.1038/onc.2013.120mailto:[email protected]://www.nature.com/onchttp://www.nature.com/oncmailto:[email protected]://dx.doi.org/10.1038/onc.2013.120


2/12

underlie certain biological processes.18,19 Notably, global genomichypoacetylation at H4K16 is a hallmark of human cancer cells,both cell lines and clinical samples.20

The biological roles of SIRT1, however, are mostly revealedthrough its deacetylation of a growing number of non-histonesubstrates that are involved in a wide variety of cellular functions,particularly in metabolic, oxidative/genotoxic and oncogenicstress responses. These substrates can be broadly categorizedas: (1) transcriptional factors p53, forkhead transcription factors(FOXO)1, FOXO3a, nuclear factor (NF)-kB, c-MYC, N-MYC, E2F1 andhypoxia-inducible transcription factors (HIF)-1a/HIF-2a, for reg-ulating cell cycle progression and promoting survival undervarious conditions; (2) DNA repair machinery elements Ku70,RAD51, NBS1, APE1, XPA/C and WRN, for improving DNA damagerepair; (3) nuclear receptor, circadian clock and related factors LXR,FXR, ERa, AR, PPARg, PGC1a, CLOCK and PER2, for regulatingmetabolism; (4) histone-modifying enzymes SUV39H1, p300, TIP60and PCAF, for regulating gene expression; (5) cell-signaling

molecules STAT3, b-catenin and SMAD7, as detailed in previousreviews.21,22

SIRT1, genetic stability and tumor suppression

Several studies using mouse models provide evidence thatSIRT1 may improve genetic stability and suppress tumorformation (Table 1). SIRT1 is a critical gene for mouse earlydevelopment. Homozygous deletion of SIRT1 (DExon56 orDExon57) results in perinatal and postnatal lethality in C57BL/6and 129 strains.23,24 More severe and early embryonic lethalityphenotype occurs in another strain with mixed geneticbackground containing FVB upon SIRT1 deletion (DExon56).25

In C57BL/6-129 background, wild-type and SIRT1/ mouseembryonic stem cells exhibit similar levels of chromosomal

abnormality, but SIRT1

/

embryonic stem cells are moreprone to genomic instability under oxidative stress.26 In mixedFVB background, SIRT1/ early embryos and mouse embryonicfibroblasts display markedly increased spontaneous grosschromosomal abnormalities accompanied with altered globalhistone modifications.25 The genetic instability in SIRT1/

embryonic cells is attributed to defective DNA damage repaircharacterized by reduced gH2AX foci formation and reducedrecruitment of DNA-damage repair factors to the foci.25,26 Inaccord with reduced genetic stability upon SIRT1 loss, SIRT1heterozygous deletion accelerates tumor formation in p53/

knock-out mice.25

Using a conditional SIRT1 overexpression allele that isspecifically expressed in the cells lining the intestine, Firesteinet al.27 showed that SIRT1 overexpression reduces intestinal tumor

formation in adenomatous polyposis coli (APC)min/ mice. Theydemonstrated that SIRT1 deacetylates b-catenin and reduces itsnuclear presence and transactivation potential. Similarly,Oberdoerffer et al.26 showed that SIRT1 conditionaloverexpression reduces tumor burden in p53/ mice. In arecent report, Herranz et al.11 undertook a 3-year study of SIRT1transgenic mice with SIRT1 overexpression under its ownpromoter, and showed that increased SIRT1 expression bythreefold improves healthy mouse aging and reducesspontaneous carcinomas and sarcomas, as well as carcinogen-induced liver cancer incidence. Taken together, in vivo mousemodels suggest that SIRT1 may improve genetic stability ofnormal cells and suppress tumor formation.

In addition to genetic stability, SIRT1 may regulate otherpathways that contribute to its tumor suppression function. SIRT1has been shown to inhibit the NF-kB pathway28 that promotesinflammation, survival and cancer metastasis.29 NF-kB comprisesheterodimers with p65 and p50 subunits. SIRT1 deacetylates thep65/Rel-A subunit of NF-kB and blocks its transactivation ofdownstream anti-apoptotic target genes, cIAP-2 and BCL-xL.28

Further in line with tumor suppressor function, SIRT1 actsdownstream of BReast CAncer 1 (BRCA1) to negatively regulatethe anti-apoptotic gene, Survivin, by deacetylating H3K9 on itspromoter and thereby repressing its transcription. Thus, BRCA1ablation, via reduced SIRT1, results in elevated Survivin levels andenhances tumor growth.30

Dysregulation of SIRT1 gene expression and enzymatic activity incancer

Although SIRT1 has tumor suppression function in the mousestudies described above, so far there is no reported functionalSIRT1 genetic mutation or deletion, or SIRT1 promoter hyper-methylation in human cancer. The Sangers Catalogue of SomaticMutations in Cancer database registers only 14 uncharacterizedpoint mutations among 4357 unique samples as of December2012, perhaps as background mutations.

In contrast to rare SIRT1 genetic alterations, numerous studieshave revealed that human cancer samples display elevated levelsof SIRT1 relative to their nontransformed counterparts. Thesestudies span different cancer types including liver,31 breast,32

gastric,33 prostate34,35 and hematopoietic3641 origin. In colorectalcancer, Kabra et al.42 observed reduction of SIRT1 expression, butNosho et al.43 showed that SIRT1 overexpression correlates withmicrosatellite instability as well as a CpG island methylatorphenotype. Similarly, in mice, overexpression of SIRT1 isreported in leukemia, lymphoma, sarcoma, lung adenocarcinomaand prostate cancer.34,39,44,45

Alteration of SIRT1 gene expression in cancer is mediated bymultiple mechanisms affecting transcription, translation and post-translational modifications. At the transcriptional level, tumorsuppressor HIC1 directly represses SIRT1 transcription, therebyleading to acetylation and activation of another tumor suppressor

p53 (Chen et al.,

44

and Figure 2). Loss of HIC1 results indeacetylation of p53 and survival of aged and damaged cells,which may predispose them to cancers.46,47 p53 itself has beenshown to directly repress SIRT1 transcription as well.48 Conversely,SIRT1 is upregulated by oncogenic transformation in severalsettings. Yuan et al.39 have recently shown that transformation ofhematopoietic stem/progenitor cells by oncogenic tyrosine kinaseBCR-ABL activates SIRT1 transcription in part through STAT5(signal transducer and activator of transcription 5). STAT5 isdownstream of numerous cytokine and growth factor receptor-signaling cascades and is constitutively active in many cancertypes.49 STAT5 also acts downstream of BCR-ABL protein inchronic myelogenous leukemia (CML).50,51 STAT5 directly bindsthe SIRT1 promoter and enhances SIRT1 expression in CML cells39

(see Figure 2). SIRT1 levels are increased stepwise from normal

747

254 495

40 294352

399137 373

31447 308

31051 301

35545 257

410100 314

SIRT1

SIRT2

SIRT3

SIRT4

SIRT5

SIRT6

SIRT7

Enzymatic

Activities

Deacetylase

Deacetylase&ART

ART

PrimaryLocalization

Nucleus

Cytosol

Mitochondria

Nucleus

Nucleolus

Mitochondria

Mitochondria

Deacetylase

Deacetylase

Deacetylase

Deacetylase&Deacylase

Sirtuin protein and catalytic domain

Figure 1. Comparison of mammalian sirtuins. The amino-acid lengthof each mature main form of sirtuins is indicated at the end of eachprotein, with the conserved catalytic domain illustrated in grey.Principal enzymatic activities and primary cellular localization areshown.

Functions of sirtuins in cancer

M Roth and WY Chen

2

Oncogene (2013), 1 12 & 2013 Macmillan Publishers Limited


3/12

hematopoietic cells to chronic-phase CML to accelerated and blastcrisis CML.39 In the same setting, Yuan et al.39 also showed thatSIRT1 can be activated by KRAS transformation. Recently, severalgroups have demonstrated that MYC (c-MYC and N-MYC) proto-oncogenes directly activates SIRT1 transcription.52,54 This occursdespite incomplete agreement of its effect on MYC proteinstability: three groups showing that SIRT1 and MYC form a positivefeedback loop in which SIRT1 deacetylates MYC and enhancesMYC protein stability,52,54,55 whereas another group showing thatSIRT1 destabilizes c-MYC protein.53 In addition, the cell cycle andapoptosis regulator E2F1 induces SIRT1 transcription when cancercells are under genotoxic stress.56

At the message level, SIRT1 expression is increased by

stabilizing its messenger RNA (mRNA) in cancer cells. MicroRNAsare small, RNA polymerase II-transcribed genes that generally formclusters and operate by binding to the 3 0 untranslated regions ofgenes and thereby negatively regulating mRNA stability and/ortranslation.57 Several families of microRNAs have been shown tonegatively regulate SIRT1, particularly miR-34a.58 Thechromosomal region where miR-34a resides is frequently lost inhuman cancers, while reintroduction of miR-34a into cancer cellstriggers apoptosis.59,60 Other miR families including miR-200a thattarget SIRT1 have been characterized as possessing tumorsuppressor function.32,57,61 Conversely, SIRT1 mRNA is stabilizedby RNA-binding protein HuR62, which has a role in promotingtumor cell proliferation and survival.6365

SIRT1 protein stability is regulated by phosphorylation, sumoy-lation and ubiquitination. SIRT1 phosphorylation by cell cycle-

dependent kinase cyclin B/CDK1 controls cell proliferation.66 Thedual specificity tyrosine phosphorylation-regulated kinasesDYRK1A and DYRK3 phosphorylate SIRT1 and increase SIRT1enzymatic activity to promote cell survival.67 SIRT1phosphorylation by c-Jun N-terminal kinase 2 stabilizes theprotein,68 whereas SIRT1 phosphorylation by JNK1 facilitatesubiqitination-mediated degradation.69 Under genotoxic stress,the proapoptotic nuclear desumoylase SENP1 removes SIRT1sumoylation and reduces its deacetylase activity.70

Finally, SIRT1 enzymatic activity could be regulated duringtumorigenesis. Deleted in breast cancer 1 (DBC1) is a tumorsuppressor that is lost in a portion of breast cancer patients. DBC1suppresses SIRT1 activity by direct binding to the SIRT1 catalytic

core domain.

71,72

In contrast, active regulator of SIRT1 (AROS)increases SIRT1 activity through direct interaction with N-terminusof SIRT1 protein.73 Furthermore, increasing SIRT1 expression isconcomitant with activation of the mammalian NAD salvagebiosynthesis enzyme nicotinamide phosphoribosyltransferase inseveral types of cancer cells to provide sufficient NAD for SIRT1functions, which is important for cancer cell survival and stressresponse.52,74

SIRT1 promotes cancer genomic instability and cancer evolution

Several recent studies provide crucial insight into the roles ofSIRT1 dysregulation in cancer. Yuan et al.39 demonstrated thatSIRT1 homozygous knockout significantly inhibits BCR-ABLtransformation of mouse bone marrow stem/progenitor cells

Table 1. Mouse cancer phenotypes with sirtuin gene knockout or overexpression

Sirtuin Genotype Phenotype Organ sites of tumors Role of sirtuins Reference

SIRT1 Constitutivedeletion of SIRT1

SIRT1 knockout inhibited BCR-ABLtransformation and CML development

Blood Cancer promoting Yuan et al.39

SIRT1tg Pten / SIRT1 transgenic mice had increasedincidence of thyroid cancer with lung

metastases. SIRT1 expression also increasedprostate carcinomas in situ

Thyroid and prostate Cancer promoting Herranz et al.75

SIRT1 / p53 / Double heterozygous knock-out mice hadincreased mammary tumor incidence

Mammary glands Cancersuppressing

Wang RH et al.25

Villin-Cre SIRT1DSTOP

APCmin/Intestinal SIRT1 expression reduced intestinaltumors

Intestine Cancersuppressing

Firestein et al.27

Mx-Cre SIRT1DSTOP

p53 /SIRT1 overexpression reduced overall tumorincidence, particularly thymic lymphoma, inp53 / background

Thymus Cancersuppressing

Oberdoerfferet al.26

SIRT1tg Transgenic SIRT1 mice had reducedincidence of spontaneous carcinomas andsarcomas, but not lymphoma. SIRT1tg micehad lower incidence of carcinogen-inducedliver carcinomas

Liver, and otherepithelial andmesenchymal tissues

Cancersuppressing

Herranz et al.11


SIRT2 / -female mice developed mammarytumors, whereas -males predominatelydeveloped liver cancers and intestinal tumors

Liver and intestine inmales and mammaryglands in females

Cancersuppressing

Kim et al.142


SIRT3 / -female mice developed mammarytumors with 35% penetrance at about 24months of age

Mammary glands Cancersuppressing

Kim et al.164

SIRT6 Constitutive SIRT6deletion

Premature aging and death at postnatalweek 3

Mostoslavskyet al.192

Villin-Cre SIRT6fl/fl

APCmin/SIRT6 / mice developed larger intestinaltumors

Intestine Cancersuppressing

Sebastianet al.200

Abbreviations: APC, adenomatous polyposis coli; CML, chronic myelogenous leukemia; SIRT, sirtuins; SIRT1 tg, SIRT1 transgenic. No tumors have been reportedin constitutive SIRT4, SIRT5 and SIRT7 knock-out mice.


M Roth and WY Chen

3

& 2013 Macmillan Publishers Limited Oncogene (2013), 1 12


4/12

and development of CML-like myeloid leukemia in a mouse modelin the BALB/c strain. In this model, bone marrow cells wereharvested from adult wild-type and SIRT1/ mice andtransduced by BCR-ABL in vitro, followed by transplantation tolethally irradiated syngenic recipients. The effect of SIRT1knockout on leukemogenesis is thus not influenced by SIRT1loss on mice, but is a result of cell autonomous impact onleukemia cells. Pharmacological inhibition of SIRT1 also inhibitsleukemia development to a similar extent as SIRT1 knockout. Thisstudy provides the first genetic evidence for a causal role ofdysregulated SIRT1 expression in efficient oncogenic trans-formation and leukemia progression.

In another study, Herranz et al.75 crossed SIRT1 transgenic miceto PTEN/ mice, and found that SIRT1 overexpression increasedincidence of thyroid carcinomas and their lung metastasis,suggesting that increased SIRT1 gene expression has a directrole in promoting tumor progression. These authors found thatSIRT1 enhanced Myc stability, although they did not directly link

deacetylation of Myc to protein stability. Furthermore, Herranzet al.75 showed that PTEN/ SIRT1 transgenic mice alsodeveloped prostate carcinomas in situ, whereas PTEN/ orSIRT1 transgenic cohort mice did not, indicating that SIRT1overexpression may also have a role in promoting tumor initiation.

This study provides additional genetic evidence that SIRT1activation can facilitate tumorigenesis.

The above studies ostensibly contrast other mouse geneticstudies suggesting roles of SIRT1 in tumor suppression, asdescribed above. The precise mechanisms for this difference arenot clear, but recent studies raise the possibility that SIRT1 mightdifferentially regulate genomic stability in normal versus cancercells (Figure 3). In normal cells, loss of SIRT1 causes defective DNArepair leading to genomic instability. Intriguingly, in cancer cells,SIRT1 knockdown also reduces the efficiency of DNA damage

repair including both non-homologous end joining (NHEJ) andhomologous recombination (HR) repair in CML cells76 andosteosarcoma cells.26 It is shown that SIRT1 is recruited to sitesof DNA damage, presumably to remodel local chromatin structureto facilitate repair in cancer cells.77,78 Therefore, it is likely thatSIRT1 may have a role in genome maintenance in both normaland cancer cells. However, this may lead to complex outcomes incancer cells. On one hand, the maintenance by SIRT1 may ensurecancer cell survival and proliferation (see more in next section) byavoiding deleterious impact of DNA damage on key oncogenes,given that transformation is accompanied with increasedproduction of reactive oxygen species (ROS) and oxidative DNAdamage.79,80 On the other hand, increased DNA repair by SIRT1could lead to more mutations in cancer cells and further genomicinstability for cancer evolution. This is supported by a recentreport by Wang et al.76, showing that SIRT1 promotes de novoacquisition of genetic mutations for drug resistance in CML andprostate cancer cells upon therapeutic (by tyrosine kinaseinhibitors) and/or genotoxic (by camptothecin) stress. SIRT1promotion of mutation acquisition is associated with its abilityto increase error-prone DNA damage repair in cancer cells, inparticular, through deacetylating the key NHEJ repair factor Ku70.Wang et al.76 proposed that the unusual effect of SIRT1 inmutation promotion may be attributed to the compromised DNArepair fidelity in cancer cells,81,82 and thus new genetic mutationsmay arise as a consequence of misrepair under stress.

Genomic instability is one of the most critical enablingcharacteristics of cancer. As cancer progresses toward higher-grade malignancy, more mutations are acquired, but mechanismsfor such increasing mutation acquisition are not well under-stood.15 The new findings by Wang et al.76 may suggest a

previously underestimated pathway for cancer genomic instabilityand evolution, that is, to accumulate mutations through enhancedinfidelity DNA repair, which has important biological significancefor cancer drug resistance. SIRT1 appears to be at the centerof such an evolution pathway;83 however, more detailedmechanisms still need to be worked out in the future.

SIRT1 promotes cancer hallmark capability

Cancer evolves not only with accumulation of genetic alterations,but also with profound epigenetic changes. Cancer cells displayglobal genomic DNA hypomethylation with concurrent hyper-methylation at tumor suppressor gene loci. In addition, cancercells display gross aberrant histone modification patterns relativeto normal cells.84 In addition to SIRT1 directly deacetylating

-1039 -178 -168 -80 -65-1116-2235 -1838

STAT5A STAT5B

STAT5HIC1 p53 Myc E2F1

BCR-ABL

catalytic coreN- -C

DBC1

254 495

AROS

AUG

UAG

HuR

AAAA

miRNAs 34a,200a, etc.

Figure 2. Regulation of SIRT1 gene expression and activities incancer cells. SIRT1 transcription is activated by Myc, E2F1 or BCR-ABLin part through STAT5, but repressed by HIC1 and p53. The sites fortranscriptional factor binding are shown. SIRT1 mRNA is stabilizedby HuR but degraded by miR34a and miR200a. SIRT1 activity isenhanced by AROS but inhibited by DBC1.

Survivalwith increased

mutations

DNA repairwith infidelity ch

emo Relapse anddrug resistance

SIRT1

DNA repairwith fidelity

Tumor

suppressionNormal Cells

Cancer Cells

SIRT1

Survival

with fixedDNA

Evolve tohigh grade

malignancy

Figure 3. A model for bifurcated SIRT1 roles in cancer throughgenome maintenance. SIRT1 promotes genome maintenance inboth normal and cancer cells under genotoxic stress and DNAdamage. Activation of DNA repair with high fidelity in normal cellsimproves genome stability and suppresses tumor formation.Activation of DNA repair with low fidelity in cancer cells preventscatastrophic genomic events and renders cancer cell survival, butallows cancer cells to accumulate nonfatal lesions and moremutations to evolve toward high-grade malignancy and drugresistance under chemotherapy.


M Roth and WY Chen

4



5/12

histone substrates to affect the epigenetic state, SIRT1 candeacetylate DNA methyltransferase 1 and can either enhance orhinder its methyltransferase activity,85 thus indirectly affectingglobal or local DNA methylation patterns. SIRT1 is a component ofthe polycomb repressor complex (PRC), which is involved insilencing genes during normal development. In cancer cells, PRC isalso involved in silencing tumor suppressor genes.86,87

The catalytic subunit of the PRC II complex is EZH2, which isresponsible for trimethylation of H3K2788 and itselfa noted proto-oncogene frequently mutated in human cancers.89 SIRT1 directlycomplexes with EZH2 and other components of thePRC complex and is an integral part of the PRCs silencingfunctions.90 Kuzmichev et al.45 identified a SIRT1-containingPRC complex, termed PRC4, which is specifically found intransformed cells and embryonic stem cells. Inhibition of SIRT1has been shown to reactivate silenced tumor suppressor genes.91

In addition, SIRT1 interacts and deacetylates the SUV39H1methyltransferase, promoting histone H3 methylation andfostering heterochromatin formation92 and repressing ribosomalRNA transcription to protect cells from energy deprivation-dependent apoptosis.93 The dysregulated epigenome by SIRT1in cancer cells may act in concert with genetic alterations tofacilitate cancer evolution and reach the biological endpointhallmarks.15 This section will discuss the cancer hallmarks that areaffected by SIRT1.

Cancer hallmark 1: resisting cell death. SIRT1 regulates multiplecell death pathways. SIRT1 deacetylates p53 at lysine 382,reducing its transcriptional activity and leading to a blockade ofp53-dependent apoptosis in response to DNA damage signals.94,95

Similar patterns are observed for p73, which is part of the p53family.96 Leukemia stem cells are typically refractory tochemotherapy. Recently, Li et al.40 have demonstrated thatinhibiting SIRT1 in CD34 CML stem/progenitor cells results inenhanced p53 acetylation, transcriptional activity and apoptosis ofthese cells, and sensitizes them to the BCR-ABL inhibitor, imatinib,both in vitro and in vivo. This effect is dependent on p53, as cellswith p53 knockdown fail to respond to SIRT1 inhibition. This studyreveals a novel drug resistance mechanism mediated by SIRT1 inleukemia stem cells.

The intrinsic apoptotic pathway is tightly orchestrated bythe BCL-2 family, which contains pro- and anti-apoptoticmembers, of which Bax is the prototypical pro-apoptotic gene.97

Cancer cells can resist apoptosis by sequestering Bax frommitochondria. This is accomplished through the non-canonicalaction of Ku70.98 SIRT1 regulates Bax sequestration throughdeacetylation of Ku70, thereby increasing Ku70 interaction withBax and blocking Bax translocation to mitochondria.99 Bymodulating Ku70, SIRT1 inhibition induces apoptosis in leukemiacells lacking p53 in vitro and suppresses growth of tumorxenograft in vivo.39

The transcriptional regulator BCL6 is also subjected todeacetylation by SIRT1.100 BCL6 is expressed in the germinal

center within lymph nodes and represses genes that are involvedin cell cycle regulation, apoptosis and differentiation.101

Translocations involving BCL6 are a frequent event in B-celllymphomas.102,103 Deacetylation by SIRT1 promotes BCL6transcriptional repression activity and resists cell apoptosis.100

Heltweg et al.104 demonstrate that a chemical inhibitor of SIRT1,cambinol, has anti-lymphoma properties in vitro and in vivo in partby preventing the deacetylation and activation of BCL6.

As described above, SIRT1 can promote cancer cell deathresistance by facilitating acquisition of genetic mutations.76 Inaddition, SIRT1 promotes chemotherapy resistance by enhancingefflux of drugs. Chu et al.105 report that SIRT1 is elevated in drug-resistant cell lines as well as in patient samples. SIRT1 increases theexpression of multidrug resistance 1 in cancer cells, whereasinhibition of SIRT1 sensitizes these cancer cells to anticancer

drugs. Another group reported that a novel SIRT1 inhibitor,Amurensin G, reduces expression of multidrug resistance 1 andsensitizes otherwise resistant cells to cytotoxic drugs.106

Cancer hallmark 2: sustaining proliferation signaling. As discussedabove, SIRT1 is activated by MYC and forms a positive feedbackloop to stabilize MYC protein in most studies. Stabilized MYCfurther enables cell proliferative signaling and stimulates cell

growth. This likely explains why Burkitts lymphoma, which isinitiated by c-MYC transformation, is most sensitive to the SIRT1inhibitor cambinol used as a single agent.104 SIRT1 is also shownto regulate WNT signaling,107 and WNT activation is associatedwith transcriptional activation of c-MYC in high-grade malignancyof colorectal cancer in the serrated route.108

Cancer hallmark 3: evading growth suppressors. As describedabove, SIRT1 deacetylates and inactivates p53, a negative cellcycle regulator, to bypass growth arrest. Another key tumorsuppressor family that is deacetylated by SIRT1 is the FOXO.109112

FOXO transcription factors are involved in cell cycle control113 aswell as antioxidant and DNA-damage repair pathways.114 Mottaet al.110 showed that SIRT1 deacetylation of FOXO3a suppresses

FOXO3-mediated cell apoptosis induction, in parallel to p53inhibition. Wang et al.115 showed that deacetylation of FOXO3 bySIRT1 or SIRT2 results in its ubiquitination and subsequentdegradation, thereby facilitating cell cycle progression andcontributing to the promotion of cancer.

Cancer hallmark 4: inducing angiogenesis. It is known that SIRT1controls endothelial angiogenic functions through deacetylatingFOXO1 and notch1 intracellular domain during vasculargrowth.116,117 SIRT1 enhances tumor angiogenesis through nega-tively modulating d-like ligand 4 (DLL4)/notch signaling in Lewislung carcinoma xenograft-derived vascular endothelial cells.118

SIRT1 also activates endothelial nitric oxide synthase bydeacetylation to enhance nitric oxide production and improvevascular function.119

Cancer hallmark 5: activating invasion and metastasis. Epithelial-to-mesenchymal transition (EMT) is an essential process to promotecancer invasion and metastasis. It has been shown that SIRT1 isactivated during EMT-like transformation of mammary epithelialcells, in part due to epigenetic silencing of miR-200a, whichnegatively regulates SIRT1.32 SIRT1 is also a positive regulator ofEMT and metastasis of prostate cancer.120 Overexpression of SIRT1induces EMT through transcription factor ZEB1 in prostate cancercells; SIRT1 knockdown restores cell-cell adhesion and reverses EMTof prostate cancer cells in vitro and in vivo.120

Cancer hallmark 6: deregulating cellular energetics and tumor

microenvironment. The HIF-1 and HIF-2 are activated in cancercells because of chronically low oxygen tension in the tumor bulk.HIF-1 activates numerous genes that promote angiogenesis,survival and glucose uptake, all necessary for tumor growth.HIF-1 is emerging as a major player in metastasis, chemo- andradiotherapy resistance.121 HIF-1a is the regulatory subunit ofHIF-1 and is subjected to post-translational modification.122,123 Limet al.124 showed that SIRT1 can deacetylate HIF-1a and repress itsbiological function in vitro and in tumor xenografts. However, sucheffect of SIRT1 on HIF-1a has been recently disputed by Laemmleet al.,125 showing that SIRT1 stabilizes HIF-1a under hypoxia andSIRT1 inhibition impairs hypoxic response of hepatocellularcarcinoma cells. The study by Laemmle et al.,125 is in line with aprevious report demonstrating that SIRT1 helps cells surviveagainst hypoxic environment by activating HIF-2a.126


M Roth and WY Chen

5



6/12

Summary of SIRT1 and cancer

All the data so far suggest that SIRT1 has both pro- and anticancerroles. We propose that SIRT1 may act as a genome caretaker innormal cells, and therefore suppress tumorigenesis. However,upon oncogenic events, tumor cells co-opt SIRT1-regulatedcellular pathways to promote unabated proliferation, progression,resisting death signals and genetic/epigenetic evolution.Such dual roles in tumorigenesis are not unprecedented. For

examples, telomerase reverse transcriptase (TERT) can both hinderand promote tumor formation;16 Transforming growth factor-bcan be antiproliferative, but is redirected toward promoting EMTand high-grade malignancy at the later stages of tumorigenesis;127

aberrant DNA hypermethylation by DNA methyltransferase 1promotes tumorigenesis by silencing tumor suppressor genes, butDNA methyltransferase 1 deletion or expression of a hypomorphicallele in mice results in tumorigenesis.128,129 As such, the preciserole of SIRT1 in tumorigenesis may be dependent on cellular andmolecular contexts.

SIRT2


SIRT2 shares certain biochemical parallels with SIRT1. SIRT2 has

thus far been characterized primarily as an NAD

-dependentprotein deacetylase. Although being mostly cytoplasmic, SIRT2can translocate to the nucleus where it deacetylates H4K16 duringmitosis.130,131 SIRT2 has also been shown to deacetylate H3K56.132

Much fewer non-histone substrates have thus far been identifiedfor SIRT2. a-tubulin is the first known SIRT2 substrate,133 but theexact biological role of tubulin acetylation/deacetylation remainselusive. Sharing substrates with SIRT1, SIRT2 also deacetylatesFOXO1,134,135 FOXO3115,136 and p53137139 for regulating auto-phagy, apoptosis and differentiation. Most recently, SIRT2 isshown to regulate programmed necrosis by targeting receptor-interacting proteins.140 Mitotic regulation is another biologicalfunction frequently ascribed to SIRT2, as detailed in a previousreview.141 Kim et al.142 described that SIRT2 regulates mitosis bydeacetylating components of the anaphase-promoting complex/

cyclosome ubiquitin ligase machinery to enhance its activity,directing degradation of aurora kinases as cells exit mitosis. In thedietary obesity setting, the intra-adipose tissue hypoxia andactivation of HIF-1a results in transcriptional repression of SIRT2,leading to increased acetylation of PGC-1a, and affectingb-oxidation and mitochondrial gene expression.143

SIRT2 and cancer

Analogous to the bifurcated results with SIRT1 in cancer, SIRT2 hasboth roles in tumor suppression and promotion. SIRT2 is reportedto be a tumor suppressor in gliomas144,145 and melanomas,146

with chromosomal loss at the SIRT2 locus and point mutationswithin the catalytic domain that abrogates its enzymatic activity.SIRT2 expression is reduced in certain cancers,142,145,147 and gene

silencing by histone deacetylation is associated with SIRT2downregulation in glioma cells.148 However, forced SIRT2expression only moderately reduces proliferation of gliomacells.149 The direct support of SIRT2s tumor suppressor role isprovided by Kim et al.,142 showing that SIRT2 knock-out micedevelop tumors in various organs due to abnormal chromosomalsegregation and aneuploidy caused by increased expression ofmitotic regulators including aurora kinases upon SIRT2 knockout.

On the other hand, it is observed that SIRT2 may promoteoncogenic phenotypes. SIRT2 is increased in acute myeloidleukemia cells compared with normal bone marrow cells, andSIRT2 inhibition causes apoptosis of acute myeloid leukemia cellsin vitro.150 Hou et al.151 showed that SIRT2 expression positivelycorrelates with cortactin in high-grade prostate cancer samplesand predicts poor prognosis. Knockdown of SIRT2 induces p53

accumulation and promotes apoptosis of cancer cells.138,139

Recently, Liu et al.152 showed that SIRT2 is activated by N-MYCin neuroblastoma cells and by c-MYC in pancreatic cancer cells.Activated SIRT2 stabilizes N-MYC and c-MYC protein and promotescell proliferation through downregulating ubiquitin-protein ligaseNEDD4. Liu et al.152 also found that SIRT2 increases Aurora Aexpression in these cells, in contrast to the finding by Kim et al.142

In this regard, it is worthy to note that Aurora A has bifurcatedroles in cancer with either gene overexpression or knockoutpromoting tumorigenesis.153,154 More studies are needed tofurther delineate the precise roles of SIRT2 in cancer.

SIRT3


SIRT3 possesses NAD -dependent deacetylase as well as ADP-ribosyltransferase activity. SIRT3 is the major mitochondrial deace-tylase with a broad range of substrates.155 Although principallylocalized to mitochondria, SIRT3 can be detected in the nucleus aswell.156 There are two forms of SIRT3, and processing of theN-terminus results in a smaller protein that localizes tomitochondria.157,158 Within the nucleus, SIRT3 deacetylates H4K16and H3K9 to repress transcription.156 In mitochondria, SIRT3

regulates metabolism, energy homeostasis, thermogenesis andmitochondrial biogenesis. For a more thorough review on SIRT3and metabolic regulation, we refer the readers to otherreviews.159,160 SIRT3 increases fatty acid b-oxidation bydeacetylating, and therefore enhancing the activity of long-chainacyl CoA dehydrogenase.161 The catabolism of fatty acids by b-oxidation yields acetyl CoA, which gets further metabolized by theKrebs cycle. SIRT3 regulates several components of the Krebs cycleand electron transport chain to promote adenosine triphosphateproduction.160,162This is punctuated by the phenotype seen in SIRT3knock-out mice that show reduced cellular adenosine triphosphatelevels as well as increased ROS.162 Uncontrolled ROS in the cellresults in DNA and protein damage, aging and cancer.163

SIRT3 and cancer

SIRT3 acts like a tumor suppressor as evidenced by increasedmammary tumor formation in SIRT3 knock-out mice.164 One majortumor suppression mechanism of SIRT3 is through modulation ofROS. As noted above, SIRT3/ cells show increased ROS due tofaulty electron transport.162,164,165 Another means by which SIRT3regulates ROS is through the activation of antioxidant enzymes,such as superoxide dismutase that is a major mitochondrialdetoxifying enzyme.166,167 Further, Someya et al.168 revealed thatSIRT3 lowers ROS by deacetylation and activation of mitochondrialisocitrate dehydrogenase 2, which in turn increases NADPH levelsand the abundance of active glutathione, a major cellularantioxidant. Deacetylation and activation of FOXO3a by SIRT3 alsopromotes its activation of antioxidant enzymes.169 Yet anothermechanism whereby SIRT3 reduces ROS, and therefore

tumorigenesis is in its capacity to destabilize HIF-1a.

165,170

Becauseof SIRT3s effect in regulating oxidative phosphorylation and HIF-1,SIRT3/ cells may be further prone to cancer by shifting itsmetabolism toward aerobic glycolysis, a phenomenon termed theWarburg effect, which is thematic of most cancer cells.171,172 Thestudies with SIRT3 knock-out mice lend credence to the notion thatSIRT3 acts to protect against tumorigenesis. However, it is unclearwhy SIRT3 knockout only increases mouse mammary tumors, giventhat these pathways are not mammary gland-specific.

In human cancers, Kim et al.164 showed that SIRT3 protein andmRNA are reduced in breast cancer. Consistently, Bell et al.165

showed that knockdown of SIRT3 in human cancer cells increasestumors size and reduces latency when injected into mice.Conversely, forced expression of SIRT3 blocks proliferation andreduces tumor xenografts. Finley et al.170 found that about 20% of


M Roth and WY Chen

6



7/12

all human cancer samples and 40% of breast and ovarian cancersamples contain deletions of SIRT3.

Recently, a novel tumor suppressor function of SIRT3 wasuncovered in its ability to deacetylate the proto-oncogene, Skp2.173

Skp2 is overexpressed in a wide range of cancers, and its expressionlevels foretell a poor clinical prognosis. Skp2 functions biochemicallyas an E3 ubiquitin ligase and is responsible for targeting numeroustumor suppressors such as p21 and p27 for proteasome-mediateddegradation.174 Deacetylation of Skp2 by SIRT3 leads to its nuclearimport where Skp2 is excluded from targeting E-cadherin. In contrast,acetylated Skp2 gets exported to the cytoplasm where itubiquitinates E-cadherin for proteasome-mediated degradation.173

Reduced E-cadherin is observed in many cancers and is a feature ofEMT and cancer metastases.175 Together, these studies indicate thatSIRT3 suppresses tumorigenesis.

Yet, as with SIRT1 and SIRT2, there are opposing studies thatpropose a tumor-promoting role for SIRT3. Alhazzazi et al.176

showed that SIRT3 levels are elevated in oral squamous carcinomacell lines and patient samples, and that knockdown of SIRT3 inOSCC lines reduces cell viability and proliferation as well as tumorsin xenografts. Ectopic SIRT3 expression reverses p53-induced cellcycle arrest and senescence, which would provide a mechanismfor a tumor-promoting role of SIRT3.177 Like SIRT1, SIRT3 candeacetylate Ku70 and thereby facilitate its interaction with Bax tomitigate Bax-mediated apoptosis.178 These studies, albeit few andcontradictory, provide some evidence that SIRT3 may have a cell-protective role under stress and may give cancer cells a growthadvantage.

SIRT4

SIRT4 is a mitochondrial ADP-ribosyltransferase without recog-nized deacetylase activity. Its primary function thus far uncoveredis in regulation of metabolic function. In vitro, SIRT4 canADP-ribosylate histones.179 SIRT4 ADP-ribosylates glutamatedehydrogenase and inhibits its catalytic activity. Glutamatedehydrogenase catalyzes the conversion of glutamate toa-ketoglutarate.179,180 Yang et al.181 reported that SIRT3 andSIRT4 are required for cell viability in response to genotoxic stressalong with nicotinamide phosphoribosyltransferase to maintainNAD levels within mitochondria.

To date, there are no systematic studies evaluating the role ofSIRT4 in cancer, although Bradbury et al.41 revealed that SIRT4levels are consistently down in acute myeloid leukemia samples.Speculatively, as SIRT4 regulates a-ketoglutarate productionfrom glutamate, we wonder what role SIRT4 may have ona-ketoglutarate-dependent enzymes that have been shown to beinvolved in tumorigenesis, such as the TET enzymes and jmjChistone demethylases.182,183 Metabolic dysfunction leading toabnormal epigenetic regulation and ultimately tumorigenesis hasa precedent, as is seen with isocitrate dehydrogenase mutations inseveral types of cancers.184,185

SIRT5

Mitochondrial SIRT5 is perhaps the most unusual of sirtuins, as itpossess NAD -dependent deacetylase as well as deacylase(demalonylase and desuccinylase) activities.4 The best studiedsubstrate of SIRT5 is carbamoyl phosphate synthetase 1 for therate-limiting step in urea synthesis. Several groups have demon-strated that SIRT5 can deacetylate, demalonylate and desucciny-late carbamoyl phosphate synthetase 1.4,186,187 Deacetylation ofcarbamoyl phosphate synthetase 1 activates its enzymatic activity,which promotes the production of urea and clearance of excessiveammonia from the cell . The biological significance ofdemolonylation and desuccinylation of carbamoyl phosphatesynthetase 1 by SIRT5 remains unknown.188 To date, there are nostudies evaluating the role of SIRT5 in tumorigenesis.

SIRT6


SIRT6 is a chromatin-bound NAD -dependent deacetylase andADP-ribosyltransferase.189 Its major histone substrates are H3K9and H3K56.190,191 Michisita et al.190 showed that SIRT6 associateswith telomeres and deacetylates H3K9 to maintain propertelomeric chromatin, and disruption of telomere functions likelyaccounts for the premature aging phenotype observed in

SIRT6

/

mice.

192

SIRT6 has an integral role in DNA repairpathways including BER,192 HR193,194 and NHEJ.195,196 SIRT6 canADP-ribosylate PARP1, leading to its activation and promotion ofdouble-strand break repair.196 Intriguingly, overexpression ofSIRT6, but not SIRT1, increases NHEJ and HR repair efficiency innonmalignant cells.196 Kawahara et al.197 demonstrated that SIRT6is recruited with NF-kB to deacetylate H3K9 and silence itstarget genes. SIRT6 is also a corepressor of HIF1 and repressesexpression of the genes involved in energy metabolism bydeacetylating H3K9.198

SIRT6 and cancer

Forced expression of SIRT6 induces apoptosis of cancer cellsbut not in nontransformed cells.199 SIRT6-mediated apoptosis

of cancer cells requires its ADP-ribosyltransferase, but notdeacetylase, activity, as well as the intact ataxia telangiectasiamutated (ATM) and p53 pathways.199 Mice with constitutive SIRT6knockout display genetic instability and die of a premature agingsyndrome B25 days postnatally.192 Using a conditional geneknock-out strategy, Sebastian et al.200 very recently demonstrateda role of SIRT6 in tumor suppression. These authors revealed thatloss of SIRT6 is sufficient to transform immortalized mouseembryonic fibroblasts. Conditional knockout of SIRT6 in theintestine of APCmin/ mice results in increased tumor incidence,in part by derepression of Myc activity and activation of aerobicglycolysis. They further showed that SIRT6 is frequently deletedand its expression is significantly reduced in human cancersamples. Together with SIRT6s roles in genome maintenance, thedata so far suggest that SIRT6 may act as a tumor suppressor.

SIRT7


SIRT7 is primarily a deacetylase and is localized to the nucleolus aswell as the nucleus.3 Within nucleoli, SIRT7 regulates ribosomalDNA gene expression in part by activating RNA polymerase I.201

SIRT7 deacetylates H3K18, specifically, to repress transcription.202

SIRT7 is also shown to deacetylate p53 in vitro and in vivo,and SIRT7 ablation increases p53-mediated apoptosis.203

SIRT7 and cancer

Several groups showed that SIRT7 is elevated in human cancers ofbreast,204 thyroid205 and liver206 origin. Ford et al.201

demonstrated that knockdown of SIRT7 inhibits cell growth andinduces apoptosis. Barber et al.202 showed that knockdown ofSIRT7 in cancer cell lines reduces cell growth both in vitro andin vivo, and demonstrated a novel oncogenic mechanism of SIRT7by deacetylating H3K18. Interestingly, many different cancersdisplay global hypoacetylation of H3K18, which is associated witha poor prognosis in prostate cancers.207,208 Viral oncogenes canstimulate hypoacetylation of H3K18.209,210 Consistently, Barberet al.202 showed that knockdown of SIRT7 abolishes adenoviralE1A-mediated proliferation and transformation of fibroblasts.

These studies point to a growth advantage that SIRT7 renderscancer cells. Further in vivo studies should be undertaken toevaluate roles of SIRT7 in cancer in the future.


M Roth and WY Chen

7



8/12

CONCLUDING REMARKS

Studies of sirtuins are rapidly growing in the field of cancer andother diseases. Sirtuins are generally involved in stress response,DNA damage repair and metabolism. SIRT1, SIRT2 and SIRT3appear to have both roles in tumor inhibition and promotion.Despite the controversy, it appears that SIRT1 has a consistent rolein mediating cancer cell survival, in particular for drug resistance,and that SIRT6 has more pronounced roles in tumor suppression.

Currently, both sirtuin activators and inhibitors have beendeveloped or under development, and they may be suited fordistinct therapeutic purposes.211 For cancer treatment, inhibitorslike tenovin-6212 and cambinol,104 which targets both SIRT1 andSIRT2, have shown antitumor effects in vivo. However, sirtuinmodulators are in general not specific and potent enough. Giventhe complex roles of each sirtuin, future effort is needed todevelop more selective sirtuin modulators for human use to treatcancer or other diseases. We expect to see continued rapid growthin sirtuin research in coming years, which will help us betterunderstand functions of this family of proteins for the good ofhuman health.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

ACKNOWLEDGEMENTS

We thank the research support from the National Cancer Institute of the

National Institutes of Health under award number R01 CA143421, and the State of

California Tobacco Related Disease Research Program (TRDRP) award 20XT-0121

to WYC. The contents are solely the responsibility of the authors and do not represent

the official views of the National Institutes of Health.

REFERENCES

1 Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and

longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000;

403: 795800.

2 Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like pro-

teins. Biochem Biophys Res Commun 2000; 273: 793798.3 Morris BJ. Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med

2012; 56: 133171.

4 Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H et al. Sirt5 is a NAD-dependent protein

lysine demalonylase and desuccinylase. Science 2011; 334: 806809.

5 Michan S, Sinclair D. Sirtuins in mammals: insights into their biological function.

Biochem J 2007; 404: 113.

6 Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in

Caenorhabditis elegans. Nature 2001; 410: 227230.

7 Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone

promote longevity in Saccharomyces cerevisiae by two different mechanisms.

Genes Dev 1999; 13: 25702580.

8 Rogina B, Helfand SL. Sir2 mediates longevity in the fly through a pathway

related to calorie restriction. Proc Natl Acad Sci USA 2004; 101: 1599816003.

9 Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG et al. Small

molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature

2003; 425: 191196.

10 Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M et al. Sirtuin activatorsmimic caloric restriction and delay ageing in metazoans. Nature 2004; 430: 686

689.

11 Herranz D, Munoz-Martin M, Canamero M, Mulero F, Martinez-Pastor B, Fer-

nandez-Capetillo O et al. Sirt1 improves healthy ageing and protects from

metabolic syndrome-associated cancer. Nat Commun 2010; 1: 3.

12 Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvari M, Piper MD et al. Absence

of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature

2011; 477: 482485.

13 Herranz D, Serrano M. SIRT1: recent lessons from mouse models. Nat Rev Cancer

2010; 10: 819823.

14 Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L et al. The sirtuin SIRT6

regulates lifespan in male mice. Nature 2012; 483: 218221.

15 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;

144: 646674.

16 Weinberg RA. The biology of cancer, 2007 Garland Science: New York 725796.

17 Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D.

Human SirT1 interacts with histone H1 and promotes formation of facultative

heterochromatin. Mol Cell 2004; 16: 93105.

18 Vaquero A. The conserved role of sirtuins in chromatin regulation. Int J Dev Biol

2009; 53: 303322.

19 Guarente L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev

2000; 14: 10211026.

20 Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G et al.

Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a

common hallmark of human cancer. Nat Genet 2005; 37: 391400.21 Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and

healthspan. Nat Rev Mol Cell Biol 2012; 13: 225238.

22 Saunders LR, Verdin E. Sirtuins: critical regulators at the crossroads between

cancer and aging. Oncogene 2007; 26: 54895504.

23 McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR et al. The

mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis.

Mol Cell Biol 2003; 23: 3854.

24 Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, Patel P et al. Developmental

defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc

Natl Acad Sci USA 2003; 100: 1079410799.

25 Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C et al. Impaired DNA damage

response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer

Cell 2008; 14: 312323.

26 Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK et al. SIRT1

redistribution on chromatin promotes genomic stability but alters gene

expression during aging. Cell 2008; 135: 907918.

27 Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J et al. The

SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth.

PLoS One 2008; 3: e2020.

28 Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA et al. Modulation of

NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.

EMBO J 2004; 23: p 23692380.

29 Wang S, Liu Z, Wang L, Zhang X. NF-kappaB signaling pathway, inflammation

and colorectal cancer. Cell Mol Immunol 2009; 6: 327334.

30 Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen Tet al. Interplay among BRCA1,

SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell 2008; 32:

1120.

31 Jang KY, Noh SJ, Lehwald N, Tao GZ, Bellovin DI, Park HS et al. SIRT1 and c-Myc

promote liver tumor cell survival and predict poor survival of human hepato-

cellular carcinomas. PLoS One 2012; 7: e45119.

32 Eades G, Yao Y, Yang M, Zhang Y, Chumsri S, Zhou Q. miR-200a regulates SIRT1

expression and epithelial to mesenchymal transition (EMT)-like transformation in

mammary epithelial cells. J Biol Chem 2011; 286: 2599226002.33 Cha EJ, Noh SJ, Kwon KS, Kim CY, Park BH, Park HS et al. Expression of DBC1 and

SIRT1 is associated with poor prognosis of gastric carcinoma. Clin Cancer Res

2009; 15: 44534459.

34 Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A et al. SIRT1

is significantly elevated in mouse and human prostate cancer. Cancer Res 2007;

67: 66126618.

35 Jung-Hynes B, Nihal M, Zhong W, Ahmad N. Role of sirtuin histone deacetylase

SIRT1 in prostate cancer. A target for prostate cancer management via its inhi-

bition? J Biol Chem 2009; 284: 38233832.

36 Kozako T, Aikawa A, Shoji T, Fujimoto T, Yoshimitsu M, Shirasawa S et al. High

expression of the longevity gene product SIRT1 and apoptosis induction by

sirtinol in adult T-cell leukemia cells. Int J Cancer 2012; 131: 20442055.

37 Wang JC, Kafeel MI, Avezbakiyev B, Chen C, Sun Y, Rathnasabapathy C et al.

Histone deacetylase in chronic lymphocytic leukemia. Oncology 2011; 81:

325329.

38 Jang KY, Hwang SH, Kwon KS, Kim KR, Choi HN, Lee NR et al. SIRT1 expression isassociated with poor prognosis of diffuse large B-cell lymphoma. Am J Surg

Pathol 2008; 32: 15231531.

39 Yuan H, Wang Z, Li L, Zhang H, Modi H, Horne D et al. Activation of stress

response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood 2012; 119:

19041914.

40 Li L, Wang L, Li L, Wang Z, Ho Y, McDonald T et al. Activation of p53 by SIRT1

inhibition enhances elimination of CML leukemia stem cells in combination with

imatinib. Cancer Cell 2012; 21: 266281.

41 Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT et al.

Histone deacetylases in acute myeloid leukaemia show a distinctive pattern

of expression that changes selectively in response to deacetylase inhibitors.

Leukemia 2005; 19: 17511759.

42 Kabra N, Li Z, Chen L, Li B, Zhang X, Wang C et al. SirT1 is an inhibitor of

proliferation and tumor formation in colon cancer. J Biol Chem 2009; 284:

1821018217.


M Roth and WY Chen

8



9/12

43 Nosho K, Shima K, Irahara N, Kure S, Firestein R, Baba Y et al. SIRT1 histone

deacetylase expression is associated with microsatellite instability and CpG

island methylator phenotype in colorectal cancer. Mod Pathol2009; 22: 922932.

44 Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB. Tumor suppressor HIC1

directly regulates SIRT1 to modulate p53-dependent DNA-damage responses.

Cell 2005; 123: 437448.

45 Kuzmichev A, Margueron R, Vaquero A, Preissner TS, Scher M, Kirmizis A et al.

Composition and histone substrates of polycomb repressive group complexes

change during cellular differentiation. Proc Natl Acad Sci USA 2005; 102:

18591864.46 Chen WY, Zeng X, Carter MG, Morrell CN, Chiu Yen RW, Esteller M et al.

Heterozygous disruption of Hic1 predisposes mice to a gender-dependent

spectrum of malignant tumors. Nat Genet 2003; 33: 197202.

47 Chen WY, Cooper TK, Zahnow CA, Overholtzer M, Zhao Z, Ladanyi M et al.

Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in

tumorigenesis. Cancer Cell 2004; 6: 387398.

48 Nemoto S, Fergusson MM, Finkel T. Nutrient availability regulates SIRT1 through

a forkhead-dependent pathway. Science 2004; 306: 21052108.

49 Hennighausen L, Robinson GW. Interpretation of cytokine signaling through the

transcription factors STAT5A and STAT5B. Genes Dev 2008; 22: 711721.

50 Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL. Constitutive activation of

STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene

1996; 13: 247254.

51 Ilaria Jr RL, Van Etten RA. P210 and P190(BCR/ABL) induce the tyrosine phos-

phorylation and DNA binding activity of multiple specific STAT family members.

J Biol Chem 1996; 271: 3170431710.52 Menssen A, Hydbring P, Kapelle K, Vervoorts J, Diebold J, Luscher B et al. The

c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1

deacetylase form a positive feedback loop. Proc Natl Acad Sci USA 2012; 109:

E187E196.

53 Yuan J, Minter-Dykhouse K, Lou Z. A c-Myc-SIRT1 feedback loop regulates cell

growth and transformation. J Cell Biol 2009; 185: 203211.

54 Marshall GM, Liu PY, Gherardi S, Scarlett CJ, Bedalov A, Xu N et al. SIRT1 pro-

motes N-Myc oncogenesis through a positive feedback loop involving the

effects of MKP3 and ERK on N-Myc protein stability. PLoS Genet 2011; 7:

e1002135.

55 Mao B, Zhao G, Lv X, Chen HZ, Xue Z, Yang B et al. Sirt1 deacetylates c-Myc and

promotes c-Myc/Max association. Int J Biochem Cell Biol 2011; 43: 15731581.

56 Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y et al. Interactions between E2F1

and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol 2006;

8: 10251031.

57 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell2004;116: 281297.

58 Yamakuchi M, Ferlito M, Lowenstein CJ. miR-34a repression of SIRT1 regulates

apoptosis. Proc Natl Acad Sci USA 2008; 105: 1342113426.

59 Welch C, Chen Y, Stallings RL. MicroRNA-34a functions as a potential tumor

suppressor by inducing apoptosis in neuroblastoma cells. Oncogene 2007; 26:

50175022.

60 Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH et al.

Transactivation of miR-34a by p53 broadly influences gene expression and

promotes apoptosis. Mol Cell 2007; 26: 745752.

61 Lages E, Guttin A, El Atifi M, Ramus C, Ipas H, Dupre I et al. MicroRNA and target

protein patterns reveal physiopathological features of glioma subtypes. PLoS

One 2011; 6: e20600.

62 Abdelmohsen K, Pullmann Jr R, Lal A, Kim HH, Galban S, Yang X et al.

Phosphorylation of HuR by Chk2 regulates SIRT1 expression. Mol Cell 2007; 25:

543557.

63 Danilin S, Sourbier C, Thomas L, Lindner V, Rothhut S, Dormoy Vet al. Role of theRNA-binding protein HuR in human renal cell carcinoma. Carcinogenesis 2010;

31: 10181026.

64 Nowotarski SL, Shantz LM. Cytoplasmic accumulation of the RNA-binding

protein HuR stabilizes the ornithine decarboxylase transcript in a murine non-

melanoma skin cancer model. J Biol Chem 2010; 285: 3188531894.

65 Heinonen M, Hemmes A, Salmenkivi K, Abdelmohsen K, Vilen ST, Laakso M et al.

Role of RNA binding protein HuR in ductal carcinoma in situ of the breast.

J Pathol 2011; 224: 529539.

66 Sasaki T, Maier B, Koclega KD, Chruszcz M, Gluba W, Stukenberg PT et al.

Phosphorylation regulates SIRT1 function. PLoS One 2008; 3: e4020.

67 Guo X, Williams JG, Schug TT, Li X. DYRK1A and DYRK3 promote cell survival

through phosphorylation and activation of SIRT1. J Biol Chem 2010; 285:

1322313232.

68 Ford J, Ahmed S, Allison S, Jiang M, Milner J. JNK2-dependent regulation of SIRT1

protein stability. Cell Cycle 2008; 7: 30913097.

69 Gao Z, Zhang J, Kheterpal I, Kennedy N, Davis RJ, Ye J. Sirtuin 1 (SIRT1) protein

degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation

contributes to hepatic steatosis in obesity. J Biol Chem 2011; 286: 2222722234.

70 Yang Y, Fu W, Chen J, Olashaw N, Zhang X, Nicosia SV et al. SIRT1 sumoylation

regulates its deacetylase activity and cellular response to genotoxic stress. Nat

Cell Biol 2007; 9: 12531262.

71 Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W. Negative regulation of the

deacetylase SIRT1 by DBC1. Nature 2008; 451: 587590.

72 Kim JE, Chen J, Lou Z. DBC1 is a negative regulator of SIRT1. Nature 2008; 451:

583586.73 Kim EJ, Kho JH, Kang MR, Um SJ. Active regulator of SIRT1 cooperates with SIRT1

and facilitates suppression of p53 activity. Mol Cell 2007; 28: 277290.

74 Wang B, Hasan MK, Alvarado E, Yuan H, Wu H, Chen WY. NAMPT overexpression

in prostate cancer and its contribution to tumor cell survival and stress response.

Oncogene 2011; 30: 907921.

75 Herranz D, Maraver A, Canamero M, Gomez-Lopez G, Inglada-Perez L, Robledo M

et al. SIRT1 promotes thyroid carcinogenesis driven by PTEN deficiency.

Oncogene (e-pub ahead of print 17 September 2012; doi: 10.1038/onc.2012.407).

76 Wang Z, Yuan H, Roth M, Stark JM, Bhatia R, Chen WY. SIRT1 deacetylase

promotes acquisition of genetic mutations for drug resistance in CML cells.

Oncogene 2013; 32: 589598.

77 OHagan HM, Mohammad HP, Baylin SB. Double strand breaks can initiate gene

silencing and SIRT1-dependent onset of DNA methylation in an exogenous

promoter CpG island. PLoS Genet 2008; 4: e1000155.

78 OHagan HM, Wang W, Sen S, Destefano Shields C, Lee SS, Zhang YW et al.

Oxidative damage targets complexes containing DNA methyltransferases, SIRT1,

and polycomb members to promoter CpG Islands. Cancer Cell2011; 20: 606619.79 Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M et al.

Mitochondrial metabolism and ROS generation are essential for Kras-mediated

tumorigenicity. Proc Natl Acad Sci USA 2010; 107: 87888793.

80 Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I, Nieborowska-Skorska

M et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to

encode imatinib resistance. Blood 2006; 108: 319327.

81 Nowicki MO, Falinski R, Koptyra M, Slupianek A, Stoklosa T, Gloc E et al. BCR/ABL

oncogenic kinase promotes unfaithful repair of the reactive oxygen species-

dependent DNA double-strand breaks. Blood 2004; 104: 37463753.

82 Slupianek A, Nowicki MO, Koptyra M, Skorski T. BCR/ABL modifies the kinetics

and fidelity of DNA double-strand breaks repair in hematopoietic cells. DNA

Repair (Amst) 2006; 5: 243250.

83 Chen WY. Accelerating cancer evolution: a dark side of SIRT1 in genome

maintenance. Oncotarget 2012; 3: 363364.

84 Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007; 128: 683692.

85 Peng L, Yuan Z, Ling H, Fukasawa K, Robertson K, Olashaw N et al. SIRT1 dea-cetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities.

Mol Cell Biol 2011; 31: 47204734.

86 Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C et al.

Epigenetic stem cell signature in cancer. Nat Genet 2007; 39: 157158.

87 Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L et al. A stem cell-like

chromatin pattern may predispose tumor suppressor genes to DNA hyper-

methylation and heritable silencing. Nat Genet 2007; 39: 237242.

88 Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P et al. Role of

histone H3 lysine 27 methylation in Polycomb-group silencing. Science 2002;

298: 10391043.

89 Chase A, Cross NC. Aberrations of EZH2 in cancer. Clin Cancer Res 2011; 17:

26132618.

90 Furuyama T, Banerjee R, Breen TR, Harte PJ. SIR2 is required for polycomb

silencing and is associated with an E(Z) histone methyltransferase complex. Curr

Biol 2004; 14: 18121821.

91 Pruitt K, Zinn RL, Ohm JE, McGarvey KM, Kang SH, Watkins DN et al. Inhibition of

SIRT1 reactivates silenced cancer genes without loss of promoter DNA hyper-methylation. PLoS Genet 2006; 2: e40.

92 Vaquero A, Scher M, Erdjument-Bromage H, Tempst P, Serrano L, Reinberg D.

SIRT1 regulates the histone methyl-transferase SUV39H1 during hetero-

chromatin formation. Nature 2007; 450: 440444.

93 Murayama A, Ohmori K, Fujimura A, Minami H, Yasuzawa-Tanaka K, Kuroda T

et al. Epigenetic control of rDNA loci in response to intracellular energy status.

Cell 2008; 133: 627639.

94 Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK et al. hSIR2(SIRT1)

functions as an NAD-dependent p53 deacetylase. Cell 2001; 107: 149159.

95 Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A et al. Negative control of p53 by

Sir2alpha promotes cell survival under stress. Cell 2001; 107: 137148.

96 Dai JM, Wang ZY, Sun DC, Lin RX, Wang SQ. SIRT1 interacts with p73 and sup-

presses p73-dependent transcriptional activity. J Cell Physiol 2007; 210: 161166.

97 Brunelle JK, Letai A. Control of mitochondrial apoptosis by the Bcl-2 family. J Cell

Sci 2009; 122(Pt 4): 437441.


M Roth and WY Chen

9

http://dx.doi.org/10.1038/onc.2012.407http://dx.doi.org/10.1038/onc.2012.407


10/12

98 Sawada M, Sun W, Hayes P, Leskov K, Boothman DA, Matsuyama S. Ku70 sup-

presses the apoptotic translocation of Bax to mitochondria. Nat Cell Biol2003; 5:

320329.

99 Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B et al. Calorie

restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase.

Science 2004; 305: 390392.

100 Bereshchenko OR, Gu W, Dalla-Favera R. Acetylation inactivates the transcrip-

tional repressor BCL6. Nat Genet 2002; 32: 606613.

101 Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM. BCL-6 represses genes that

function in lymphocyte differentiation, inflammation, and cell cycle control.Immunity 2000; 13: 199212.

102 Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K, Chaganti RS et al. Alterations of a

zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 1993;

262: 747750.

103 Kerckaert JP, Deweindt C, Tilly H, Quief S, Lecocq G. and C. BastardLAZ3, a novel

zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 trans-

locations in human lymphomas. Nat Genet 1993; 5: 6670.

104 Heltweg B, Gatbonton T, Schuler AD, Posakony J, Li H, Goehle S et al. Antitumor

activity of a small-molecule inhibitor of human silent information regulator 2

enzymes. Cancer Res 2006; 66: 43684377.

105 Chu F, Chou PM, Zheng X, Mirkin BL, Rebbaa A. Control of multidrug resistance

gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1.

Cancer Res 2005; 65: 1018310187.

106 Oh WK, Cho KB, Hien TT, Kim TH, Kim HS, Dao TT et al. Amurensin G, a potent

natural SIRT1 inhibitor, rescues doxorubicin responsiveness via down-regulation

of multidrug resistance 1. Mol Pharmacol 2010; 78: 855864.

107 Holloway KR, Calhoun TN, Saxena M, Metoyer CF, Kandler EF, Rivera CA et al.SIRT1 regulates dishevelled proteins and promotes transient and constitutive

Wnt signaling. Proc Natl Acad Sci USA 2010; 107: 92169221.

108 Kriegl L, Vieth M, Kirchner T, Menssen A. Up-regulation of c-MYC and SIRT1

expression correlates with malignant transformation in the serrated route to

colorectal cancer. Oncotarget 2012; 3: 11821193.

109 Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Yet al. Stress-dependent

regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004;

303: 20112015.

110 Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W et al. Mammalian

SIRT1 represses forkhead transcription factors. Cell 2004; 116: 551563.

111 van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH,

Burgering BM. FOXO4 is acetylated upon peroxide stress and deacetylated by

the longevity protein hSir2(SIRT1). J Biol Chem 2004; 279: 2887328879.

112 Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M et al. Silent

information regulator 2 potentiates Foxo1-mediated transcription through its

deacetylase activity. Proc Natl Acad Sci USA 2004; 101: 1004210047.113 Ho KK, Myatt SS, Lam EW. Many forks in the path: cycling with FoxO. Oncogene

2008; 27: 23002311.

114 Dansen TB, Burgering BM. Unravelling the tumor-suppressive functions of FOXO

proteins. Trends Cell Biol 2008; 18: 421429.

115 Wang F, Chan CH, Chen K, Guan X, Lin HK, Tong Q. Deacetylation of FOXO3 by

SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation.

Oncogene 2012; 31: 15461557.

116 Guarani V, Deflorian G, Franco CA, Kruger M, Phng LK, Bentley K et al.

Acetylation-dependent regulation of endothelial notch signalling by the SIRT1

deacetylase. Nature 2011; 473: 234238.

117 Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F et al.

SIRT1 controls endothelial angiogenic functions during vascular growth. Genes

Dev 2007; 21: 26442658.

118 Xie M, Liu M, He CS. SIRT1 regulates endothelial notch signaling in lung cancer.

PLoS One 2012; 7: e45331.

119 Mattagajasingh I, Kim CS, Naqvi A, Yamamori T, Hoffman TA, Jung SB et al. SIRT1

promotes endothelium-dependent vascular relaxation by activating endothelialnitric oxide synthase. Proc Natl Acad Sci USA 2007; 104: 1485514860.

120 Byles V, Zhu L, Lovaas JD, Chmilewski LK, Wang J, Faller DV et al. SIRT1 induces

EMT by cooperating with EMT transcription factors and enhances prostate

cancer cell migration and metastasis. Oncogene 2012; 31: 46194629.

121 Monti E, Gariboldi MB. HIF-1 as a target for cancer chemotherapy, chemo-

sensitization and chemoprevention. Curr Mol Pharmacol 2011; 4: 6277.

122 Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M et al. HIFalpha targeted for

VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

Science 2001; 292: 464468.

123 Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ et al. Targeting of

HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated

prolyl hydroxylation. Science 2001; 292: 468472.

124 Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW. Sirtuin 1 modulates cellular

responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell

2010; 38: 864878.

125 Laemmle A, Lechleiter A, Roh V, Schwarz C, Portmann S, Furer C et al. Inhibition

of SIRT1 impairs the accumulation and transcriptional activity of HIF-1alpha

protein under hypoxic conditions. PLoS One 2012; 7: e33433.

126 Dioum EM, Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD et al. Regulation

of hypoxia-inducible factor 2 alpha signaling by the stress-responsive deacety-

lase sirtuin 1. Science 2009; 324: 12891293.

127 Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer pro-

gression. Nat Rev Cancer 2010; 10: 415424.

128 Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R. DNA hypo-

methylation leads to elevated mutation rates. Nature 1998; 395: 8993.129 Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors

promoted by DNA hypomethylation. Science 2003; 300: 455.

130 Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW et al. SirT2 is a histone

deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev

2006; 20: 12561261.

131 North BJ, Verdin E. Interphase nucleo-cytoplasmic shuttling and localization of

SIRT2 during mitosis. PLoS One 2007; 2: e784.

132 Das C, Lucia MS, Hansen KC, Tyler JK. CBP/p300-mediated acetylation of histone

H3 on lysine 56. Nature 2009; 459: 113117.

133 North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2

ortholog, SIRT2, is an NAD -dependent tubulin deacetylase. Mol Cell 2003; 11:

437444.

134 Jing E, Gesta S, Kahn CR. SIRT2 regulates adipocyte differentiation through

FoxO1 acetylation/deacetylation. Cell Metab 2007; 6: 105114.

135 Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S et al. Cytosolic FoxO1 is essential

for the induction of autophagy and tumour suppressor activity. Nat Cell Biol

2010; 12: 665675.136 Wang F, Nguyen M, Qin FX, Tong Q. SIRT2 deacetylates FOXO3a in response to

oxidative stress and caloric restriction. Aging Cell 2007; 6: 505514.

137 Jin YH, Kim YJ, Kim DW, Baek KH, Kang BY, Yeo CYet al. Sirt2 interacts with 14-3-

3 beta/gamma and down-regulates the activity of p53. Biochem Biophys Res

Commun 2008; 368: 690695.

138 Li Y, Matsumori H, Nakayama Y, Osaki M, Kojima H, Kurimasa A et al. SIRT2

down-regulation in HeLa can induce p53 accumulation via p38 MAPK activation-

dependent p300 decrease, eventually leading to apoptosis. Genes Cells 2011; 16:

3445.

139 Peck B, Chen CY, Ho KK, Di Fruscia P, Myatt SS, Coombes RC et al. SIRT inhibitors

induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2.

Mol Cancer Ther 2010; 9: 844855.

140 Narayan N, Lee IH, Borenstein R, Sun J, Wong R, Tong G et al. The NAD-

dependent deacetylase SIRT2 is required for programmed necrosis. Nature 2012;

492: 199204.

141 Inoue T, Hiratsuka M, Osaki M, Oshimura M. The molecular biology of mam-malian SIRT proteins: SIRT2 in cell cycle regulation. Cell Cycle 2007; 6: 10111018.

142 Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X et al. SIRT2 maintains

genome integrity and suppresses tumorigenesis through regulating APC/C

activity. Cancer Cell 2011; 20: 487499.

143 Krishnan J, Danzer C, Simka T, Ukropec J, Walter KM, Kumpf S et al. Dietary

obesity-associated Hif1alpha activation in adipocytes restricts fatty acid oxida-

tion and energy expenditure via suppression of the Sirt2-NAD system. Genes

Dev 2012; 26: 259270.

144 Nahhas F, Dryden SC, Abrams J, Tainsky MA. Mutations in SIRT2 deacetylase

which regulate enzymatic activity but not its interaction with HDAC6 and

tubulin. Mol Cell Biochem 2007; 303: 221230.

145 Hiratsuka M, Inoue T, Toda T, Kimura N, Shirayoshi Y, Kamitani H et al.

Proteomics-based identification of differentially expressed genes in human

gliomas: down-regulation of SIRT2 gene. Biochem Biophys Res Commun 2003;

309: 558566.

146 Lennerz V, Fatho M, Gentilini C, Frye RA, Lifke A, Ferel D et al. The response of

autologous T cells to a human melanoma is dominated by mutated neoantigens.Proc Natl Acad Sci USA 2005; 102: 1601316018.

147 Peters CJ, Rees JR, Hardwick RH, Hardwick JS, Vowler SL, Ong CA et al. A 4-gene

signature predicts survival of patients with resected adenocarcinoma of the

esophagus, junction, and gastric cardia. Gastroenterology2010; 139: 19952004.

148 Inoue T, Hiratsuka M, Osaki M, Yamada H, Kishimoto I, Yamaguchi S et al. SIRT2, a

tubulin deacetylase, acts to block the entry to chromosome condensation in

response to mitotic stress. Oncogene 2007; 26: 945957.

149 North BJ, Verdin E. Mitotic regulation of SIRT2 by cyclin-dependent kinase

1-dependent phosphorylation. J Biol Chem 2007; 282: 1954619555.

150 Dan L, Klimenkova O, Klimiankou M, Klusman JH, van den Heuvel-Eibrink MM,

Reinhardt D et al. The role of sirtuin 2 activation by nicotinamide phosphor-

ibosyltransferase in the aberrant proliferation and survival of myeloid leukemia

cells. Haematologica 2012; 97: 551559.

151 Hou H, Chen W, Zhao L, Zuo Q, Zhang G, Zhang X et al. Cortactin is associated

with tumour progression and poor prognosis in prostate cancer and SIRT2


M Roth and WY Chen

10



11/12

other than HADC6 may work as facilitator in situ. J Clin Pathol 2012; 65:

10881096.

152 Liu PY, Xu N, Malyukova A, Scarlett CJ, Sun YT, Zhang XD et al. The histone

deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death Differ 2012; 20:

503514.

153 Lu LY, Wood JL, Ye L, Minter-Dykhouse K, Saunders TL, Yu X et al. Aurora A is

essential for early embryonic development and tumor suppression. J Biol Chem

2008; 283: 3178531790.

154 Wang X, Zhou YX, Qiao W, Tominaga Y, Ouchi M, Ouchi Tet al. Overexpression of

aurora kinase A in mouse mammary epithelium induces genetic instabilitypreceding mammary tumor formation. Oncogene 2006; 25: 71487158.

155 Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R et al.

Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetyla-

tion. Mol Cell Biol 2007; 27: 88078814.

156 Scher MB, Vaquero A, Reinberg D. SirT3 is a nuclear NAD -dependent histone

deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev

2007; 21: 920928.

157 Cooper HM, Huang JY, Verdin E, Spelbrink JN. A new splice variant of the mouse

SIRT3 gene encodes the mitochondrial precursor protein. PLoS One 2009; 4:

e4986.

158 Schwer B, North BJ, Frye RA, Ott M, Verdin E. The human silent information

regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine

dinucleotide-dependent deacetylase. J Cell Biol 2002; 158: 647657.

159 Huang JY, Hirschey MD, Shimazu T, Ho L, Verdin E. Mitochondrial sirtuins.

Biochim Biophys Acta 2010; 1804: 16451651.

160 Verdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria:energy production, apoptosis, and signaling. Trends Biochem Sci 2010; 35:

669675.

161 Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB et al. SIRT3

regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.

Nature 2010; 464: 121125.

162 Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A et al. A role for the

mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl

Acad Sci USA 2008; 105: 1444714452.

163 Tudek B, Winczura A, Janik J, Siomek A, Foksinski M, Olinski R. Involvement of

oxidatively damaged DNA and repair in cancer development and aging. Am J

Transl Res 2010; 2: 254284.

164 Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD et al.

SIRT3 is a mitochondria-localized tumor suppressor required for maintenance

of mitochondrial integrity and metabolism during stress. Cancer Cell 2010; 17:

4152.

165 Bell EL, Emerling BM, Ricoult SJ, Guarente L. SirT3 suppresses hypoxia induciblefactor 1alpha and tumor growth by inhibiting mitochondrial ROS production.

Oncogene 2011; 30: 29862996.

166 Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H et al.

Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates

MnSOD activity in response to stress. Mol Cell 2010; 40: 893904.

167 Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces

oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 2010; 12:

662667.

168 Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C et al. Sirt3

mediates reduction of oxidative damage and prevention of age-related hearing

loss under caloric restriction. Cell 2010; 143: 802812.

169 Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP.

Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-

dependent antioxidant defense mechanisms in mice. J Clin Invest 2009; 119:

27582771.

170 Finley LW, Carracedo A, Lee J, Souza A, Egia A, Zhang J et al. SIRT3 opposesreprogramming of cancer cell metabolism through HIF1alpha destabilization.

Cancer Cell 2011; 19: 416428.

171 Warburg O. On the origin of cancer cells. Science 1956; 123: 309314.

172 Haigis MC, Deng CX, Finley LW, Kim HS, Gius D. SIRT3 is a mitochondrial tumor

suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg

effect, and carcinogenesis. Cancer Res 2010; 72: 24682472.

173 Inuzuka H, Gao D, Finley LW, Yang W, Wan L, Fukushima H et al. Acetylation-

dependent regulation of Skp2 function. Cell 2012; 150: 179193.

174 Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2 and

beta-TrCP: tipping the scales of cancer. Nat Rev Cancer 2008; 8: 438449.

175 Tiwari N, Gheldof A, Tatari M, Christofori G. EMT as the ultimate survival

mechanism of cancer cells. Semin Cancer Biol 2012; 22: 194207.

176 Alhazzazi TY, Kamarajan P, Joo N, Huang JY, Verdin E, DSilva NJ et al. Sirtuin-3

(SIRT3), a novel potential therapeutic target for oral cancer.. Cancer 2011; 117:

16701678.

177 Li S, Banck M, Mujtaba S, Zhou MM, Sugrue MM, Walsh MJ. p53-induced growth

arrest is regulated by the mitochondrial SirT3 deacetylase. PLoS One 2010; 5:

e10486.

178 Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB, Gupta MP. SIRT3 is a

stress-responsive deacetylase in cardiomyocytes that protects cells from

stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol 2008; 28:

63846401.

179 Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ

et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie

restriction in pancreatic beta cells. Cell 2006; 126: 941954.180 Herrero-Yraola A, Bakhit SM, Franke P, Weise C, Schweiger M, Jorcke D et al.

Regulation of glutamate dehydrogenase by reversible ADP-ribosylation in

mitochondria. Embo J 2001; 20: 24042412.

181 Yang H, Yang T, Baur JA, Perez E, Matsui T, Carmona JJ et al. Nutrient-sensitive

mitochondrial NAD levels dictate cell survival. Cell 2007; 130: 10951107.

182 Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H et al. Inhibition of alpha-KG-dependent

histone and DNA demethylases by fumarate and succinate that are accumulated

in mutations of FH and SDH tumor suppressors. Genes Dev2012; 26: 13261338.

183 Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH et al. Oncometabolite 2-hydro-

xyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxy-

genases. Cancer Cell 2011; 19: 1730.

184 Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al. Leukemic

IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt

TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18:

553567.

185 Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O et al. IDH mutationimpairs histone demethylation and results in a block to cell differentiation.

Nature 2012; 483: 474478.

186 Ogura M, Nakamura Y, Tanaka D, Zhuang X, Fujita Y, Obara A et al.

Overexpression of SIRT5 confirms its involvement in deacetylation and activa-

tion of carbamoyl phosphate synthetase 1. Biochem Biophys Res Commun 2010;

393: 7378.

187 Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 Deacetylates carbamoyl

phosphate synthetase 1 and regulates the urea cycle. Cell 2009; 137: 560570.

188 Newman JC, He W, Verdin E. Mitochondrial protein acylation and intermediary

metabolism: regulation by sirtuins and implications for metabolic disease. J Biol

Chem 2012; 287: 4243642443.

189 Liszt G, Ford E, Kurtev M, Guarente L. Mouse Sir2 homolog SIRT6 is a nuclear

ADP-ribosyltransferase. J Biol Chem 2005; 280: 2131321320.

190 Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M et al. SIRT6

is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature

2008; 452: 492496.191 Michishita E, McCord RA, Boxer LD, Barber MF, Hong T, Gozani O et al. Cell cycle-

dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6.

Cell Cycle 2009; 8: 26642666.

192 Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L et al.

Genomic instability and aging-like phenotype in the absence of mammalian

SIRT6. Cell 2006; 124: 315329.

193 Kaidi A, Weinert BT, Choudhary C, Jackson SP. Human SIRT6 promotes DNA end

resection through CtIP deacetylation. Science 2010; 329: 13481353.

194 Mao Z, X. Tian M, Meter Van, Ke Z, Gorbunova V, Seluanov A. Sirtuin 6 (SIRT6)

rescues the decline of homologous recombination repair during replicative

senescence. Proc Natl Acad Sci USA 2012; 109: 1180011805.

195 McCord RA, Michishita E, Hong T, Berber E, Boxer LD, Kusumoto R et al. SIRT6

stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand

break repair. Aging (Albany NY) 2009; 1: 1091

2013 roth and chen oncogene review

Documents