Identification of a novel SIRT7 inhibitor as anticancer drug candidate
Identification of a novel SIRT7 inhibitor as anticancer drug candidate
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DOI：
10.1016/j.bbrc.2018.11.120
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发表时间：
2019-01-08
影响因子：
3.1
通讯作者：
Kim, Kwang Rol
中科院分区：
文献类型：
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作者：
Kim, Ji-Hye;Kim, Dahee;Kim, Kwang Rol
SIRT 1 -7是一类脱乙酰基酶，在酵母和哺乳动物的DNA损伤修复、衰老和代谢中发挥重要作用。SIRT 7定位于核仁中。它调节细胞过程，包括基因组稳定性、rDNA转录和细胞增殖，并在肿瘤发生中发挥作用。SIRT 7使其底物组蛋白H3（在赖氨酸18处）和p53脱乙酰基。p53是一种肿瘤抑制因子，诱导细胞凋亡或细胞周期停滞，并通过乙酰化稳定。通过SIRT 7在K382处的p53脱乙酰化通过减弱p53活性来抑制癌细胞生长。因此，鉴定新型SIRT 7酶抑制剂是重要的。在这项研究中，我们发现了一种新的SIRT 7抑制剂（ID：97491），以剂量依赖性方式降低SIRT 7活性。ID：97491通过抑制SIRT 7诱导p53的表达及其乙酰化。此外，ID：97491通过胱天蛋白酶相关蛋白上调凋亡作用并抑制体内癌症生长。研究结果表明，ID：97491可以是抑制SIRT 7的脱乙酰酶活性并通过在K373/382处乙酰化增加p53稳定性来预防肿瘤进展的潜在候选物。(C)2018由Elsevier Inc.出版
Sirtuins (SIRT1-7), a class of deacetylases, play major roles in DNA damage repair, aging, and metabolism in yeast and in mammals. SIRT7 is localized in the nucleolus. It regulates cellular processes, including genomic stability, rDNA transcription, and cell proliferation, and plays a role in tumorigenesis. SIRT7 deacetylates its substrates histone H3 (at lysine 18) and p53. p53, a tumor suppressor, induces apoptosis or cell cycle arrest and is stabilized by acetylation. p53 deacetylation at K382 by SIRT7 suppressed cancer cell growth by attenuating p53 activity. Therefore, identification of novel SIRT7 enzyme inhibitors is important. In this study, we found a novel inhibitor of SIRT7 (ID: 97491) that decreased SIRT7 activity in a dose-dependent manner. ID: 97491 induced expression of p53 and its acetylation by inhibited SIRT7. Moreover, ID: 97491 upregulated apoptotic effects through the caspase related proteins and inhibited cancer growth in vivo. The study results suggest that ID: 97491 can be a potential candidate to inhibit the deacetylase activity of SIRT7 and prevent tumor progression by increasing p53 stability through acetylation at K373/382. (C) 2018 Published by Elsevier Inc.