Division of Innovative Target Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, South Korea; Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, South Korea.
Division of Bio Platform Technology Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, South Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 350-764, South Korea.
Biochem Biophys Res Commun. 2019 Jan 8;508(2):451-457. doi: 10.1016/j.bbrc.2018.11.120. Epub 2018 Nov 30.
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.
Sirtuins（SIRT1-7）是一类去乙酰化酶，在酵母和哺乳动物中在 DNA 损伤修复、衰老和代谢中发挥重要作用。SIRT7 定位于核仁。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。SIRT7 去乙酰化其底物组蛋白 H3（赖氨酸 18）和 p53。p53 是一种肿瘤抑制因子，可诱导细胞凋亡或细胞周期停滞，并通过乙酰化稳定。SIRT7 对 K382 的 p53 去乙酰化通过减弱 p53 活性抑制癌细胞生长。因此，鉴定新型 SIRT7 酶抑制剂很重要。在这项研究中，我们发现了一种新型的 SIRT7 抑制剂（ID：97491），它可剂量依赖性地降低 SIRT7 活性。ID：97491 通过抑制 SIRT7 诱导 p53 的表达及其乙酰化。此外，ID：97491 通过半胱氨酸天冬氨酸蛋白酶相关蛋白上调凋亡作用，并抑制体内肿瘤生长。研究结果表明，ID：97491 可以通过增加 p53 在 K373/382 处的乙酰化来抑制 SIRT7 的去乙酰化活性，并通过增加 p53 的稳定性来预防肿瘤进展。
