Identification of a cellularly active SIRT6 allosteric activator
Identification of a cellularly active SIRT6 allosteric activator
复制标题
细胞活性 SIRT6 变构激活剂的鉴定
DOI：
10.1038/s41589-018-0150-0
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发表时间：
2018-12-01
影响因子：
14.8
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Huang, Zhimin;Zhao, Junxing;Zhang, Jian
SIRT 6是SIRT脱乙酰酶家族的成员，负责组蛋白H3 N-乙酰基-赖氨酸9（H3 K9 ac）和56（H3 K56 ac）的脱乙酰化。作为一种肿瘤抑制因子，SIRT 6经常被发现在各种癌症中具有低表达。在这里，我们报告了MDL-800的鉴定，MDL-800是一种选择性SIRT 6激活剂。MDL-800通过与变构位点结合使SIRT 6的脱乙酰酶活性增加高达22倍;这种相互作用导致人肝细胞癌（HCC）细胞中H3 K9 ac和H3 K56 ac水平的总体降低。因此，MDL-800通过SIRT 6驱动的细胞周期停滞抑制HCC细胞的增殖，并且在肿瘤异种移植模型中有效。总之，这些数据表明SIRT 6的药理学活化是治疗HCC的潜在治疗方法。MDL-800是一种一流的小分子细胞SIRT 6激活剂，可用于生理学和病理学研究SIRT 6脱乙酰化的作用。
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.