ONX-0914 Suppresses Hormone-Sensitive Prostate Cancer by Promoting O-GlcNAcylation-Mediated Stabilization of TCF7L1

作者：Peng Xian, Zhenwei Feng, Haitao Yu, Hubin Yin, Haonan Chen, Tenglin Shi, Xilai Li, Chunlin Zhang, Xuesong Bai, Xin Gou, Xinyuan Li, Jie Jack Li · 发表于：Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · 年份：2026 · DOI：10.32604/or.2026.073156 · 被引用次数：1 · 研究领域：Glycosylation and Glycoproteins Research、Cancer, Hypoxia, and Metabolism、Cancer, Lipids, and Metabolism

Objective: Androgen receptor (AR) signaling is a central driver of prostate cancer progression, yet the metabolic and transcriptional mechanisms regulating AR expression remain incompletely characterized. This study investigated whether the immunoproteasome inhibitor ONX-0914 suppresses hormone-sensitive prostate cancer (HSPC) through metabolic modulation of AR and aimed to identify the transcriptional mediator involved. Methods: HSPC and castration-resistant prostate cancer models were used to evaluate the effects of ONX-0914 on cell proliferation, invasion, migration, and epithelial–mesenchymal transition. Xenograft assays, bioinformatic screening, and analyses of O-GlcNAcylation and protein stability were performed, together with quantitative polymerase chain reaction (qPCR) and Western blotting. Results: ONX-0914 markedly suppressed hormone-sensitive prostate cancer (HSPC) progression through both LMP7-dependent and LMP7-independent mechanisms. Mechanistically, ONX-0914 activated the hexosamine biosynthetic pathway and enhanced global O-GlcNAcylation, leading to stabilization of the transcriptional repressor Transcription factor 7–like 1 (TCF7L1) and consequent suppression of androgen receptor (AR) expression. Functionally, activation of the O-GlcNAcylation–TCF7L1 axis inhibited cell proliferation, invasion, migration, and epithelial–mesenchymal transition in vitro. In vivo, TCF7L1 overexpression, particularly under conditions of enhanced O-GlcNAcylation, significantly su...