作者
Zhimin Huang,Junxing Zhao,Wei Deng,Yuanchang Chen,Jialin Shang,Kun Song,Lenan Zhang,C. Wang,Shaoyong Lu,Xiuyan Yang,Bin He,Jinrong Min,Hao Hu,Mengyao Tan,Jianrong Xu,Q. Zhang,Jie Zhong,Xian-He Sun,Zhiyong Mao,Hou-Wen Lin,Mingzhe Xiao,Y. Eugene Chin,Hualiang Jiang,Ying Xu,G. Chen,Jun Zhang
摘要
SIRT6, a member of the SIRT deacetylase family, is responsible for deacetylation of histone H3 Ne-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.