A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity

Jing, Hui; Hu, Jing; He, Bin; Abril, Yashira L. Negrón; Stupinski, Jack; Weiser, Keren; Carbonaro, Marisa; Chiang, Ying-Ling; Southard, Teresa; Giannakakou, Paraskevi; Weiss, Robert S.; Lin, Hening

doi:10.1016/j.ccell.2016.02.007

Cited by 203 publications

(257 citation statements)

References 57 publications

(82 reference statements)

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“…Recent reports using a selective SIRT2 inhibitor demonstrated that SIRT2 inhibition exhibits anti-tumor activity against breast cancer cells by degrading c-Myc oncoprotein. 8) Our results support this observation, as two selective SIRT2 inhibitors, RK-9123016 and SirReal2, 7) inhibited cell growth of human breast cancer MCF-7 cells accompanied by c-Myc degradation (Fig. 2), although their chemical structures are completely different.…”

Section: Resultssupporting

confidence: 77%

“…8) Therefore, we examined the effect of RK-9123016 on cell viability of MCF-7 cells by measuring cellular amounts of ATP. Consistent with previous results, RK-9123016 as well as SirReal2 reduced the viability of MCF-7 cells in a concentration-dependent manner ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…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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confidence: 99%

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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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Section: Resultssupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Importantly, SIRT2 inhibition in these BLBC cells caused the loss of the basal differentiation phenotype, colony-forming ability, and invasiveness characteristic of aggressive BLBC, ultimately resulting in diminished tumorigenic capability. Interestingly, a recent study demonstrated that selective SIRT2 inhibition has broad anti-cancer effects, in part by promoting the proteasomal degradation of the c-Myc oncoprotein (Jing et al, 2016). Notably in this study, several BLBC cancer cells also exhibited sensitivity to SIRT2 inhibition despite no observable decrease of c-Myc, suggesting that destabilization of other cancer-relevant substrates of SIRT2, such as Slug, may contribute to this anti-cancer effect in BLBCs.…”

Section: Discussionmentioning

confidence: 99%

The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer

Zhou

Wronski

et al. 2016

Cell Reports

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Summary Overabundance of Slug protein is common in human cancer and represents an important determinant underlying the aggressiveness of basal-like breast cancer (BLBC). Despite its importance, this transcription factor is rarely mutated in BLBC, and the mechanism of its deregulation in cancer remains unknown. Here we report that Slug undergoes acetylation-dependent protein degradation and identify the deacetylase SIRT2 as a key mediator of this post-translational mechanism. SIRT2 inhibition rapidly destabilizes Slug, whereas SIRT2 overexpression extends Slug stability. We show that SIRT2 deacetylates Slug protein at lysine residue K116 to prevent Slug degradation. Interestingly, SIRT2 is frequently amplified and highly expressed in BLBC. Genetic depletion and pharmacological inactivation of SIRT2 in BLBC cells reverse Slug stabilization, cause the loss of clinically relevant pathological features of BLBC, and inhibit tumor growth. Our results suggest that targeting SIRT2 may be a rational strategy for diminishing Slug abundance and its associated malignant traits in BLBC.

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“…S. Kim et al, 2011) or oncoprotein (P. Y. Liu et al, 2013) is controversial, many studies have observed anti-tumorigenic effects through SirT2 inhibition (Cheon, Kim, Choi, & Kim, 2015; Jing et al, 2016; Peck et al, 2010; Y. Zhang et al, 2009).…”

Section: Small Molecule Wild-type P53 Activatorsmentioning

confidence: 99%

Reviving the guardian of the genome: Small molecule activators of p53

Nguyen

Liao

Zeng

et al. 2017

Pharmacology & Therapeutics

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The tumor suppressor p53 is one of the most important proteins for protection of genomic stability and cancer prevention. Cancers often inactivate it by either mutating its gene or disabling its function. Thus, activating p53 becomes an attractive approach for the development of molecule-based anti-cancer therapy. The past decade and half have witnessed tremendous progress in this area. This essay offers readers with a grand review on this progress with updated information about small molecule activators of p53 either still at bench work or in clinical trials.

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A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity

Cited by 203 publications

References 57 publications

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

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

The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer

Reviving the guardian of the genome: Small molecule activators of p53

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