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

Xiaoqun Shan(单晓群), Rong Jiang, Dongmei Gou, Jin Xiang, Peng Zhou, Jie Xia, Kai Wang, Ailong Huang, Ni Tang, Luyi Huang

摘要Abstract

O-GlcNAcylation (O-linked β-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 catalyzes 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.

Keywords: O-GlcNAc transferase inhibitor （OGTi），CDK9， c-Myc， hepatocellular carcinoma，O-GlcNAc modifacation

关键词： OGT抑制剂，细胞周期素依赖性激酶9，原癌基因c-Myc, 肝细胞肝癌/肝癌，O-GlcNAc糖基化修饰(氧连接N-乙酰葡萄糖胺修饰)

DOI: https://doi.org/10.1111/febs.16877

全文链接: https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.16877