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

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.

Automated summary

O-GlcNAcylation is a crucial cellular process that is involved in various physiological processes. OGT is the only enzyme responsible for transferring O-GlcNAc to nucleocytoplasmic proteins. Abnormal glycosylation by OGT is associated with multiple diseases. This study identified a novel diketopiperazine-based OGT inhibitor called HLY838, which effectively decreases cellular O-GlcNAc levels and enhances the anti-HCC activity of CDK9 inhibitor by regulating c-Myc and E2F1 expression. These findings suggest the potential of OGT inhibitors as sensitizing agents in cancer therapeutics.