Lysine-5 Acetylation Negatively Regulates Lactate Dehydrogenase A and Is Decreased in Pancreatic Cancer

Zhao, Di; Zou, Shao Wu; Liu, Ying; Zhou, Xin; Mo, Yan; Wang, Ping; Xu, Yan; Dong, Bo; Xiong, Yue; Lei, Qun-Ying; Guan, Kun Liang

doi:10.1016/j.ccr.2013.02.005

Cited by 271 publications

(230 citation statements)

References 39 publications

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“…14) In contrast, growing evidence suggests that SIRT2 promotes tumorigenesis. [15][16][17][18][19] The reason for this discrepancy is unknown, but it may depend on cancer progression stage or cell type. Recent reports using a selective SIRT2 inhibitor demonstrated that SIRT2 inhibition exhibits anti-tumor activity against breast cancer cells by degrading c-Myc oncoprotein.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…For example, SIRT5-mediated deacetylation of carbanoyl phosphate synthetase 1 (CPS1) upregulates its activity to increase amino acid catabolism (37). Acetylation of lactate dehydrogenase A (LDH-A) on lysine residue 5 (K5) inhibits its enzyme activity and promotes its degradation via chaperone-mediated autophagy (CMA) (22). Under high-glucose conditions, the gluconeogenic rate-limiting enzyme phosphoenolpyruvate carboxykinase (PEPCK1) is hyperacetylated, which promotes its ubiquitylation and degradation (19).…”

Section: Discussionmentioning

confidence: 99%

“…Patients were excluded if alcohol consumption was more than 40 g/day for men and more than 20 g/day for women and if other liver diseases were detected by serological testing and imaging studies. Paraffin-embedded liver tissue was cut, deparaffinized, and hydrated, and immunohistochemistry was performed as described previously (22). Images were captured using a charge-coupled device camera and analyzed using Image-Pro Plus software.…”

mentioning

confidence: 99%

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Guo

Zhou

Wei

et al. 2016

Molecular and Cellular Biology

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bNonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein ␣-subunit (MTP␣) functions as a critical enzyme for fatty acid ␤-oxidation, but whether dysregulation of MTP␣ is pathogenically connected to NAFLD is poorly understood. We show that MTP␣ is acetylated at lysine residues 350, 383, and 406 (MTP␣-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTP␣-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTP␣. Replacement of MTP␣-3K with either MTP␣-3KR or MTP␣-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTP␣-3K mutant expression in mouse livers, and MTP␣-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTP␣ and MTP␣-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTP␣ regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD.

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“…To generate a homogenously K353-acetylated ALDH1A1 construct, we used a 3-plasmid system as previously described (38). This system allows for the site-specific incorporation of N-acetyllysine by way of a Methanosarcina barkeri acetyl-lysyl-tRNAsynthetase/tRNACUA pair that recognizes the amber codon.…”

Section: Methodsmentioning

confidence: 99%

NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells

Zhao¹,

Mo²,

Li³

et al. 2014

J. Clin. Invest.

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104

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Lysine-5 Acetylation Negatively Regulates Lactate Dehydrogenase A and Is Decreased in Pancreatic Cancer

Cited by 271 publications

References 39 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

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells

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