The Histone Deacetylase SIRT6 Is a Tumor Suppressor that Controls Cancer Metabolism

Sebastián, Carlos; Zwaans, Bernardette M. M.; Silberman, Dafne M.; Gymrek, Melissa; Goren, Alon; Zhong, Lei; Ram, Oren; Truelove, Jessica; Guimarães, Alexander R.; Toiber, Debra; Cosentino, Claudia; Greenson, Joel K.; MacDonald, Alasdair A.; McGlynn, Liane; Maxwell, Fraser; Edwards, Joanne; Giacosa, Sofía; Guccione, Ernesto; Weissleder, Ralph; Bernstein, B; Regev, Aviv; Shiels, Paul G.; Lombard, David B.; Mostoslavsky, Raúl

doi:10.1016/j.cell.2012.10.047

Cited by 580 publications

(655 citation statements)

References 58 publications

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“…These enzymes act as deacetylases, desuccinylases and demalonylases, and at least two members of the Sirtuin family, SirT5 and SirT6, have been implicated in GLS regulation. Sebastian et al showed that SirT6 represses MYC, and, by extension, the expression of GLS [112]. A more direct interaction was demonstrated by Poletta and colleagues, who used immunoprecipitation assays to show that GLS binds directly to SirT5 [113].…”

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confidence: 89%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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Many cancer cells exhibit an altered metabolic phenotype, in which glutamine consumption is upregulated relative to healthy cells. This metabolic reprogramming often depends upon mitochondrial glutaminase activity, which converts glutamine to glutamate, a key precursor for biosynthetic and bioenergetic processes. Two isozymes of glutaminase exist, a kidney-type (GLS) and a liver-type enzyme (GLS2 or LGA). While a majority of studies have focused on GLS, here we summarize key findings on both glutaminases, describing their structure and function, their roles in cancer and pharmacological approaches to inhibiting their activities.

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confidence: 89%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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“…Mechanistically, SIRT6 suppresses aerobic glycolysis and Mycdependent ribosome biosynthesis, and lack of this sirtuin leads to robust metabolic reprogramming, sufficient to promote tumorigenesis. In line with this, Sirt6 expression is down-regulated in human pancreatic and colorectal cancers, and conditional deletion of Sirt6 promotes intestinal tumorigenesis in vivo (106). Consistent with a tumor-suppressive function, it has recently been shown that overexpression of SIRT6 induces apoptosis in cancer cell lines (55).…”

Section: Cancermentioning

confidence: 59%

“…As noted above, SIRT6 is a key regulator of glucose metabolism, and lack of this chromatin factor leads to a phenotype that is reminiscent of the Warburg effect (37). Indeed, SIRT6 has been recently described as a tumor suppressor that regulates cancer metabolism (106). Mechanistically, SIRT6 suppresses aerobic glycolysis and Mycdependent ribosome biosynthesis, and lack of this sirtuin leads to robust metabolic reprogramming, sufficient to promote tumorigenesis.…”

Section: Cancermentioning

confidence: 99%

From Sirtuin Biology to Human Diseases: An Update

Sebastián

Satterstrom

Haigis

et al. 2012

Journal of Biological Chemistry

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210

159

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Originally rising to notoriety for their role in the regulation of aging, sirtuins are a family of NAD ؉ -dependent enzymes that have been connected to a steadily growing set of biological processes. In addition to regulating aging, sirtuins play key roles in the maintenance of organismal metabolic homeostasis. These enzymes also have primarily protective functions in the development of many age-related diseases, including cancer, neurodegeneration, and cardiovascular disease. In this minireview, we provide an update on the known roles for each of the seven mammalian sirtuins in these areas.Over three-quarters of a century ago, Clive McCay and colleagues first noted that rats kept on a calorie-restricted diet lived longer than freely fed controls (1). Despite the length of time that has elapsed since this discovery, the molecular mechanism that drives this life span extension has remained elusive. Originally described as a silencing factor in yeast (silencing information regulator), the protein Sir2 came out on top in a screen for modulators of yeast life span (2). Moreover, Sir2 was required for the life span of yeast to be extended by calorie restriction (3). These discoveries launched a new field in biology: the study of Sir2 and its homologs in mammals, called sirtuins.Mammals have seven sirtuins (SIRT1-7) that possess NAD ϩ -dependent deacetylase, deacylase, and ADP-ribosyltransferase activities (4). Sirtuins are found in different subcellular locations, including the nucleus (SIRT1, SIRT6, and SIRT7), cytosol (SIRT2), and mitochondria (SIRT3-5), although in some studies, SIRT1 has been found to possess cytosolic activities, and SIRT2 has been found to associate with nuclear proteins. Sirtuins have important functions in a diverse yet interrelated set of physiological processes. In this minireview, we discuss research done in the past four years featuring their roles in aging, metabolism, cancer biology, cardiovascular disease, inflammation, and brain pathology. AgingFollowing the first publication describing a role for yeast Sir2 in promoting longevity (2), many laboratories focused on elucidating whether sirtuins might play similar roles in other organisms. Sirtuins have been shown to regulate life span in lower organisms, including yeast, nematodes, and fruit flies (5), although their role in worm and fly life span has recently been debated (6, 7). Most of these studies have described a key role for SIRT1 in regulating the metabolic response to calorie restriction (CR) 5 (8), a dietary intervention that robustly extends life span across numerous species. However, wholebody overexpression of SIRT1 in mice does not affect life span (9). Nevertheless, SIRT1 does appear to promote healthy aging by protecting against several age-related pathologies (10).The strongest link between mammalian sirtuins and the antiaging effects of CR comes from SIRT3, which mediates the prevention of age-related hearing loss by CR (11). Hearing loss is a hallmark of mammalian aging and is characterized by a gradual loss of spiral...

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“…SIRT6-deficient mice have a striking degenerative phenotype leading to shortened lifespan and are associated with hypoglycemia and defects in DNA repair (2). Deletion of SIRT6 is sufficient to promote tumorigenesis independent of oncogene activation (3). SIRT6 overexpression lowers LDL and triglyceride levels, improves glucose tolerance (4), and increases lifespan of male mice (5).…”

mentioning

confidence: 99%

Activation of the Protein Deacetylase SIRT6 by Long-chain Fatty Acids and Widespread Deacylation by Mammalian Sirtuins

Feldman

Baeza

Denu

2013

Journal of Biological Chemistry

587

707

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Background: Sirtuins regulate metabolism, genome maintenance, and stress responses. Results: Long-chain free fatty acids stimulate SIRT6 deacetylase, and sirtuins display distinct but overlapping specificity for diverse acylated peptides. Conclusion: SIRT6 is activated by biologically relevant fatty acids, and long-chain deacylation is a general feature of sirtuins. Significance: Discovery of endogenous, small-molecule activators of SIRT6 demonstrates the therapeutic potential of compounds that promote SIRT6 function.

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The Histone Deacetylase SIRT6 Is a Tumor Suppressor that Controls Cancer Metabolism

Cited by 580 publications

References 58 publications

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

From Sirtuin Biology to Human Diseases: An Update

Activation of the Protein Deacetylase SIRT6 by Long-chain Fatty Acids and Widespread Deacylation by Mammalian Sirtuins

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