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Identification of a novel SIRT7 inhibitor as anticancer drug candidate

Author:
Kim, Ji-Hye, Kim, Dahee, Cho, Suk Joon, Jung, Kwan-Young, Kim, Jong-Hoon, Lee, Jun Mi, Jung, Hee Jung, Kim, Kwang Rok
Source:
Biochemical and biophysical research communications 2019 v.508 no.2 pp. 451-457
ISSN:
0006-291X
Subject:
DNA repair, acetylation, antineoplastic agents, apoptosis, carcinogenesis, caspases, cell cycle checkpoints, cell growth, cell nucleolus, cell proliferation, dose response, enzyme activity, enzyme inhibition, enzyme inhibitors, genomics, histones, lysine, mammals, metabolism, neoplasm cells, neoplasms, ribosomal DNA, transcription (genetics), yeasts
Abstract:
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.
Agid:
6225561