期刊
NATURE CHEMICAL BIOLOGY
卷 14, 期 12, 页码 1118-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-018-0150-0
关键词
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资金
- National Basic Research Program of China (973 Program) [2015CB910403]
- National Natural Science Foundation of China [81721004, 91753117, 81322046, 81302698, 31671459, U1605221, 2181001006]
- Program for Changjiang Scholars
- Innovative Research Team of the University of the Ministry Education of China
- CAS Interdisciplinary Innovation Team
- Innovation Program of the Shanghai Municipal Education Commission
- State Key Laboratory of Luminescence and application [SKLA-2016-12]
- Strategic Priority Research Program of the Chinese Academy of Sciences, 'Personalized Medicines-Molecular Signature-based Drug Discovery and Development' [XDA12040100]
SIRT6, a member of the SIRT deacetylase family, is responsible for deacetylation of histone H3 N-epsilon-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.
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