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Nat Chem Biol. 2018 Dec;14(12):1118-1126. doi: 10.1038/s41589-018-0150-0. Epub 2018 Oct 29.

Identification of a cellularly active SIRT6 allosteric activator.

Author information

1
Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, Department of Pathophysiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
2
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
3
Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guizhou Medical University, Guiyang, China.
4
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
5
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
6
School of Life Sciences and Technology, Tongji University, Shanghai, China.
7
Basic Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
8
Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, Department of Pathophysiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. yingxuxu@shsmu.edu.cn.
9
Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, Department of Pathophysiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. chengq@shsmu.edu.cn.
10
Key Laboratory of Cell Differentiation and Apoptosis, Ministry of Education, Department of Pathophysiology, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. jian.zhang@sjtu.edu.cn.
11
Basic Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. jian.zhang@sjtu.edu.cn.
12
Medicinal Bioinformatics Center, Shanghai JiaoTong University School of Medicine, Shanghai, China. jian.zhang@sjtu.edu.cn.

Abstract

SIRT6, a member of the SIRT deacetylase family, is responsible for deacetylation of histone H3 Nε-acetyl-lysines 9 (H3K9ac) and 56 (H3K56ac). As a tumor suppressor, SIRT6 has frequently been found to have low expression in various cancers. Here, we report the identification of MDL-800, a selective SIRT6 activator. MDL-800 increased the deacetylase activity of SIRT6 by up to 22-fold via binding to an allosteric site; this interaction led to a global decrease in H3K9ac and H3K56ac levels in human hepatocellular carcinoma (HCC) cells. Consequently, MDL-800 inhibited the proliferation of HCC cells via SIRT6-driven cell-cycle arrest and was effective in a tumor xenograft model. Together, these data demonstrate that pharmacological activation of SIRT6 is a potential therapeutic approach for the treatment of HCC. MDL-800 is a first-in-class small-molecule cellular SIRT6 activator that can be used to physiologically and pathologically investigate the roles of SIRT6 deacetylation.

PMID:
30374165
DOI:
10.1038/s41589-018-0150-0
[Indexed for MEDLINE]

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