SIRT2 as a Therapeutic Target for Age-Related Disorders

Oliveira, Rita Machado de; Sarkander, Jana; Kazantsev, Aleksey G.; Outeiro, Tiago F.

doi:10.3389/fphar.2012.00082

Cited by 114 publications

(90 citation statements)

References 106 publications

(137 reference statements)

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“…Both tumor-suppressive and tumor-promoting functions have been attributed to Sirt1 and Sirt2 (31,47,48). The common view, supported by knock-out experiments in mice, is that sirtuins can delay tumor formation by maintaining genome integrity (20).…”

Section: Discussionmentioning

confidence: 99%

Sirt2 Deacetylase Is a Novel AKT Binding Partner Critical for AKT Activation by Insulin

Gopalakrishnan

Davaakhuu

Kaplun

et al. 2014

Journal of Biological Chemistry

112

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Background: AKT kinases mediate insulin signaling downstream of phosphatidylinositol-3 kinase (PI3K). Results: AKT binds Sirt2 in insulin-responsive cells and Sirt2 inhibition blocks AKT activation, whereas Sirt2 overexpression sensitizes cells to insulin. Conclusion: Sirt2 deacetylase is an essential factor in AKT activation. Significance: Sirt2 modulators could be useful in treatment of diseases involving AKT, such as type 2 diabetes and cancer.

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Section: Discussionmentioning

confidence: 99%

Sirt2 Deacetylase Is a Novel AKT Binding Partner Critical for AKT Activation by Insulin

Gopalakrishnan

Davaakhuu

Kaplun

et al. 2014

Journal of Biological Chemistry

112

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“…30 Hence, we evaluated whether increase in SIRT2 levels during senescence is also accompanied by changes in acetylation status of its downstream targets. As expected, the increase in SIRT2 levels during senescence was also associated with deacetylation of its targets, a-tubulin at lysine 40, histone H4 at lysine 16 (H4K16) and p65 at lysine 310 ( Fig.…”

Section: Sirt2 Overexpression Leads To Deacetylation Of Its Substratementioning

confidence: 99%

Increased expression of SIRT2 is a novel marker of cellular senescence and is dependent on wild type p53 status

2016

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Sirtuins (SIRT) belonging to the NADC dependent histone deacetylase III class of enzymes have emerged as master regulators of metabolism and longevity. However, their role in prevention of organismal aging and cellular senescence still remains controversial. In the present study, we now report upregulation of SIRT2 as a specific feature associated with stress induced premature senescence but not with either quiescence or cell death. Additionally, increase in SIRT2 expression was noted in different types of senescent conditions such as replicative and oncogene induced senescence using multiple cell lines. Induction of SIRT2 expression during senescence was dependent on p53 status as depletion of p53 by shRNA prevented its accumulation. Chromatin immunoprecipitation revealed the presence of p53 binding sites on the SIRT2 promoter suggesting its regulation by p53, which was also corroborated by the SEAP reporter assay. Overexpression or knockdown of SIRT2 had no effect on stress induced premature senescence, thereby indicating that SIRT2 increase is not a cause of senescence; rather it is an effect linked to senescence-associated changes. Overall, our results suggest SIRT2 as a promising marker of cellular senescence at least in cells with wild type p53 status.

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“…Cell Viability Assay MCF-7 cells (1×10 3 ) were grown in a 96-well plate and treated with dimethyl sulfoxide (DMSO) or compounds for 96 h. Cell viability was measured by the ATPlite luminescence assay system (PerkinElmer, Inc., Waltham, MA, U.S.A.) using a Synergy H4 hybrid reader (BioTek, Tokyo, Japan).…”

Section: )mentioning

confidence: 99%

Identification of a Selective SIRT2 Inhibitor and Its Anti-breast Cancer Activity

Shah

Ito

Nakata

et al. 2016

Biological & Pharmaceutical Bulletin

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SIRT2 is a member of the human sirtuin family of proteins and possesses nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity. SIRT2 has been involved in various cellular processes including gene transcription, genome constancy, and the cell cycle. In addition, SIRT2 is deeply implicated in diverse diseases including cancer. In this study, we identified a small molecule inhibitor of SIRT2 with a structure different from known SIRT2 inhibitors by screening from a chemical library. The hit compound showed a high selectivity toward SIRT2 as it only inhibited SIRT2, and not other sirtuins including SIRT1 and SIRT3 or zinc-dependent histone deacetylases (HDACs) including HDAC1 and HDAC6, in vitro. The compound increased the acetylation level of eukaryotic translation initiation factor 5A (eIF5A), a physiological substrate of SIRT2, and reduced cell viability of human breast cancer cells accompanied with a decrease in c-Myc expression. These results suggest that the compound is cellular effective and has potential for development as a therapeutic agent against breast cancers by specific inhibition of SIRT2.Key words SIRT2; c-Myc; breast cancer; high-throughput screening; eukaryotic translation initiation factor 5ASirtuins are a family of nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylases shown to play biological and physiological roles in diverse cellular processes such as metabolism, transcription, and DNA repair. Mammals have seven sirtuins that display different subcellular localizations and functions. SIRT2 is a predominantly cytosolic protein and was originally reported as a microtubule deacetylase, 1) but further studies have revealed that SIRT2 acts as a deacetylase for histones and a number of non-histone proteins. This wide variety of substrates might be correlated with physiological roles of SIRT2 in diverse biological processes such as the cell cycle, autophagy, and energy metabolism. 2)Many studies suggest an important involvement of SIRT2 in neurodegeneration, inflammation, bacterial infection, and cancer, and that modulation of SIRT2 activity could be novel strategy for therapies against these disorders.3-5) However, pharmacological evidence for SIRT2 as a valid therapeutic target has not yet been shown. Therefore, potent and selective SIRT2 inhibitors are required for initial proof of concept studies. Although there are several reports describing SIRT2 inhibitors to date, 6) specificity and cellular potency of most present SIRT2 inhibitors appear to be insufficient for elucidating in vivo SIRT2 functions. In this regard, development of potent and highly specific SIRT2 inhibitors has been recently achieved. 7,8) Here, we identified a potent and specific SIRT2 inhibitor by high-throughput screening. Because the fundamental structure of the compound is different from that of existing SIRT2 inhibitors, it may serve as a novel class of chemical tool for exploring SIRT2 functions in cells.

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SIRT2 as a Therapeutic Target for Age-Related Disorders

Cited by 114 publications

References 106 publications

Sirt2 Deacetylase Is a Novel AKT Binding Partner Critical for AKT Activation by Insulin

Sirt2 Deacetylase Is a Novel AKT Binding Partner Critical for AKT Activation by Insulin

Increased expression of SIRT2 is a novel marker of cellular senescence and is dependent on wild type p53 status

Identification of a Selective SIRT2 Inhibitor and Its Anti-breast Cancer Activity

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