Identification of a diketopiperazine-based O-GlcNAc transferase inhibitor sensitizing hepatocellular carcinoma to CDK9 inhibition

作者全名："Shan, Xiaoqun; Jiang, Rong; Gou, Dongmei; Xiang, Jin; Zhou, Peng; Xia, Jie; Wang, Kai; Huang, Ailong; Tang, Ni; Huang, Luyi"

作者地址："[Shan, Xiaoqun; Gou, Dongmei; Xiang, Jin; Zhou, Peng; Xia, Jie; Wang, Kai; Huang, Ailong; Tang, Ni; Huang, Luyi] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Minist, Chongqing 400010, Peoples R China; [Jiang, Rong] Chongqing Med Univ, Lab Stem Cell & Tissue Engn, Chongqing, Peoples R China"

通信作者："Tang, N; Huang, LY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Minist, Chongqing 400010, Peoples R China."

来源：FEBS JOURNAL

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001000367600001

JCR分区：Q1

影响因子：5.5

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：CDK9; c-Myc; hepatocellular carcinoma; inhibitor; O-GlcNAc transferase

摘要："O-GlcNAcylation (O-linked beta-N-acetylglucosaminylation) is an important post-translational and metabolic process in cells that is implicated in a wide range of physiological processes. O-GlcNAc transferase (OGT) is ubiquitously present in cells and is the only enzyme that catalyses the transfer of O-GlcNAc to nucleocytoplasmic proteins. Aberrant glycosylation by OGT has been linked to a variety of diseases including cancer, neurodegenerative disorders and diabetes. Previously, we and others demonstrated that O-GlcNAcylation is notably elevated in hepatocellular carcinoma (HCC). The overexpression of O-GlcNAcylation promotes cancer progression and metastasis. Here, we report the identification of HLY838, a novel diketopiperazine-based OGT inhibitor with the ability to induce a global decrease in cellular O-GlcNAc. HLY838 enhances the in vitro and in vivo anti-HCC activity of CDK9 inhibitor by downregulating c-Myc and downstream E2F1 expression. Mechanistically, c-Myc is regulated by the CDK9 at the transcript level, and stabilized by OGT at the protein level. This work therefore demonstrates that HLY838 potentiates the antitumor responses of CDK9 inhibitor, providing an experimental rationale for developing OGT inhibitor as a sensitizing agent in cancer therapeutics."

基金机构："National Natural Science Foundation of China [U20A20392, 82272975, 82072286]; 111 Project [D20028]; Science and Technology Research Program of Chongqing Municipal Education Commission [HZ2021006]; Chongqing PhD ""Through Train"" Scientific Research Project [CSTB2022BSXM-JCX0052]; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University; Future Medical Youth Innovation Team of Chongqing Medical University [W0036, W0101]; Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau) [2023DBXM007]; Sichuan Science and Technology Program [2022YFH0027]"

基金资助正文："Support for this research was provided by the National Natural Science Foundation of China (U20A20392, 82272975, 82072286); the 111 Project (No. D20028), the Science and Technology Research Program of Chongqing Municipal Education Commission (HZ2021006); Chongqing PhD ""Through Train"" Scientific Research Project (CSTB2022BSXM-JCX0052); the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University; and the Future Medical Youth Innovation Team of Chongqing Medical University (W0036, W0101); Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2023DBXM007); Sichuan Science and Technology Program (2022YFH0027)."