Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer

Kugel, Sita; Feldman, Jessica L.; Klein, Milton M.; Silberman, Dafne M.; Sebastián, Carlos; Mermel, Craig H.; Dobersch, Stephanie; Clark, Allison; Getz, Gad; Denu, John M.; Mostoslavsky, Raúl

doi:10.1016/j.celrep.2015.09.022

Cited by 66 publications

(71 citation statements)

References 21 publications

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“…Recently, SIRT6 mutations were found in several tumor types such as non-small-cell lung cancer, renal clear cell carcinoma, cervical carcinoma, and melanoma[19]. Since naturally occurring tumor-associated mutations in SIRT6 were shown to alter its stability, localization, and/or enzymatic activity[19], we checked SIRT6 status in HCC tissues and cell lines using several public databases such as COSMIC (Catalogue of Somatic Mutations in Cancer, http://cancer.sanger.ac.uk/cosmic) and Cancer Genome Atlas (https://tcga-data.nci.nih.gov/docs/publications/tcga/).…”

Section: Resultsmentioning

confidence: 99%

“…Since naturally occurring tumor-associated mutations in SIRT6 were shown to alter its stability, localization, and/or enzymatic activity[19], we checked SIRT6 status in HCC tissues and cell lines using several public databases such as COSMIC (Catalogue of Somatic Mutations in Cancer, http://cancer.sanger.ac.uk/cosmic) and Cancer Genome Atlas (https://tcga-data.nci.nih.gov/docs/publications/tcga/). Regarding HCC cell lines used for our experiments, mutation status of SK-Hep1 Huh-7, SNU475 and SNU449 could be obtained from COSMIC.…”

Section: Resultsmentioning

confidence: 99%

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SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

Lee

Ryu

Kwon³

et al. 2016

PLoS ONE

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The role of Sirtuin 6 (SIRT6) as a tumor suppressor or oncogene in liver cancer remains controversial. Thus, we identified the specific role of SIRT6 in the progression of hepatocellular carcinoma (HCC). SIRT6 expression was significantly higher in HCC cell lines and HCC tissues from 138 patients than in an immortalized hepatocyte cell line, THLE-2 and non-tumor tissues, respectively. SIRT6 knockdown by shRNA suppressed the growth of HCC cells and inhibited HCC tumor growth in vivo. In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners. Microarray analysis revealed that the expression of genes involved in nucleosome assembly was apparently altered in SIRT6-depleted Hep3B cells. SIRT6 knockdown promoted G2/M phase arrest and downregulation of genes encoding histone variants associated with nucleosome assembly, which could be attributed to DNA damage. Taken together, our findings suggest that SIRT6 acts as a tumor promoter by preventing DNA damage and cellular senescence, indicating that SIRT6 represents a potential therapeutic target for the treatment of HCC.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

Lee

Ryu

Kwon³

et al. 2016

PLoS ONE

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“…No significant levels of SIRT6 could be detected at the STAT3 target promoters over the time course of metabolic stress in HepG2 control, SIRT6kd, or SIRT6/PKM2 doubleknockdown cells. We also examined the effect of PKM2 on SIRT6-mediated regulation of previously described SIRT6 target genes (4,7,10). We observed that wild-type PKM2 and the constitutively nuclear PKM2 K433Q mutant had no effect on SIRT6 occupancy at the promoters of known SIRT6 target genes (Fig.…”

Section: H133ymentioning

confidence: 92%

“…Elevated c-JUN levels in hepatocellular carcinoma down-regulate SIRT6 expression in a c-FOS-dependent manner (8). Recently, naturally occurring cancer-associated point mutations were identified in SIRT6 that result in its loss of tumor-suppressor functions (10). However, the role of SIRT6 enzymatic activities in its tumorsuppressor functions is not well understood.…”

mentioning

confidence: 99%

SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions

Bhardwaj

Das

2016

Proc. Natl. Acad. Sci. U.S.A.

121

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SIRT6 (sirtuin 6) is a member of sirtuin family of deacetylases involved in diverse processes including genome stability, metabolic homeostasis, and tumorigenesis. However, the role of SIRT6 deacetylase activity in its tumor-suppressor functions is not well understood. Here we report that SIRT6 binds to and deacetylates nuclear PKM2 (pyruvate kinase M2) at the lysine 433 residue. PKM2 is a glycolytic enzyme with nonmetabolic nuclear oncogenic functions. SIRT6-mediated deacetylation results in PKM2 nuclear export. We further have identified exportin 4 as the specific transporter mediating PKM2 nuclear export. As a result of SIRT6-mediated deacetylation, PKM2 nuclear protein kinase and transcriptional coactivator functions are abolished. Thus, SIRT6 suppresses PKM2 oncogenic functions, resulting in reduced cell proliferation, migration potential, and invasiveness. Furthermore, studies in mouse tumor models demonstrate that PKM2 deacetylation is integral to SIRT6-mediated tumor suppression and inhibition of metastasis. Additionally, reduced SIRT6 levels correlate with elevated nuclear acetylated PKM2 levels in increasing grades of hepatocellular carcinoma. These findings provide key insights into the pivotal role of deacetylase activity in SIRT6 tumor-suppressor functions.) is a member of the highly conserved sirtuin family of NAD + -dependent enzymes and plays a key role in DNA repair, telomere maintenance, and cellular metabolic processes. It exhibits diverse enzymatic activities including NAD + -dependent deacetylation and mono-ADP ribosylation. SIRT6 deacetylates telomeric histone H3 at lysine 9 (H3K9) and lysine 56 residues (H3K56) (1, 2). SIRT6-mediated deacetylation of telomeric H3K9 is required for the stable association of the Werner syndrome protein with telomeric chromatin for proper telomere function. SIRT6 also interacts with the NF-κB RELA subunit, deacetylates H3K9 at NF-κB target gene promoters, and attenuates NF-κB-mediated apoptosis and senescence (3). Likewise, SIRT6 also binds to hypoxia-inducible factor 1-alpha (HIF1α), deacetylates H3K9 at HIF1α target gene promoters, and regulates glucose homeostasis (4). SIRT6 also interacts with and deacetylates CtIP [C-terminal binding protein (CtBP) interacting protein] to promote the repair of DNA double-strand breaks by homologous recombination (5). SIRT6 mono-ADP ribosylates PARP1 to stimulate the repair of DNA double-strand breaks in response to oxidative stress (6).Several recent studies report that SIRT6 functions as a tumor suppressor. It was observed that loss of SIRT6 promotes tumor formation even without the activation of known oncogenes (7). Furthermore, SIRT6 was found to be down-regulated in pancreatic and colorectal cancers. Down-regulation of SIRT6 also has been reported in hepatocellular carcinoma (8, 9). Elevated c-JUN levels in hepatocellular carcinoma down-regulate SIRT6 expression in a c-FOS-dependent manner (8). Recently, naturally occurring cancer-associated point mutations were identified in SIRT6 that result in its loss of tumor-su...

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“…Interestingly, Sirt6 has very low in-vitro histone deacetylase activity but is activated up to 35-fold by select long-chain fatty acids (LCFAs), including myristic, oleic, and linoleic acid (95). Sirt6 plays a role in genome stability and glucose homeostasis, and loss of Sirt6 function plays a role in the metabolic switch that occurs in human tumors (102,103). …”

Section: Regulation Of Chromatin Modification By Endogenous Metabolitmentioning

confidence: 99%

Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin

Krautkramer

Dhillon

Denu

et al. 2017

Translational Research

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The mammalian gut microbiota has been linked to host developmental, immunologic, and metabolic outcomes. This collection of trillions of microbes inhabits the gut and produces a myriad of metabolites, which are measurable in host circulation and contribute to the pathogenesis of human diseases. The link between endogenous metabolite availability and chromatin regulation is a well-established and active area of investigation, however, whether microbial metabolites can elicit similar effects is less understood. In this review, we focus on seminal and recent research that establishes chromatin regulatory roles for both endogenous and microbial metabolites. We also highlight key physiologic and disease settings where microbial metabolite-host chromatin interactions have been established and/or may be pertinent.

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Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer

Cited by 66 publications

References 21 publications

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions

Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin

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