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ARTICLE

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

Peng Xian1,2,#, Zhenwei Feng1,3,#, Haitao Yu3, Hubin Yin1,3, Haonan Chen1, Tenglin Shi1, Xilai Li1,3, Chunlin Zhang1,3, Xuesong Bai1,3, Xin Gou1,*, Xinyuan Li1,3,*, Jie Li1,*
1 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
2 Department of Urological Oncology, Chongqing University Cancer Hospital, Chongqing, China
3 Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China
* Corresponding Author: Xin Gou. Email: email; Xinyuan Li. Email: email; Jie Li. Email: email
# These authors contributed equally to this work as the first author
(This article belongs to the Special Issue: Molecular Mechanisms of Urogenital Cancers)

Oncology Research https://doi.org/10.32604/or.2026.073156

Received 11 September 2025; Accepted 09 February 2026; Published online 02 March 2026

Abstract

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 suppressed tumor growth and AR expression. Conclusion: This study identifies a novel ONX-0914/HBP/TCF7L1 O-GlcNAcylation axis that metabolically stabilizes TCF7L1, leading to repression of AR signaling and inhibition of HSPC progression. These findings reveal a previously unrecognized metabolic–transcriptional regulatory mechanism and highlight TCF7L1 O-GlcNAcylation as a potential therapeutic target in AR-dependent prostate cancer.

Keywords

Prostate cancer; transcription factor 7–like 1 (TCF7L1); androgen receptor; O-GlcNAcylation; hexosamine biosynthetic pathway

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