Ubiquitination-Androgen Receptor Coupling in Prostate Cancer Therapeutics.

Abstract

Prostate cancer is one of the most frequently diagnosed malignancies in men and a leading cause of cancer-related mortality worldwide. The androgen receptor (AR) remains the principal driver of prostate cancer progression and castration-resistant prostate cancer (CRPC), with its stability, localization, and transcriptional activity being tightly regulated by the ubiquitin-proteasome system (UPS). E3 ubiquitin ligases and deubiquitinases (DUBs) critically govern AR turnover and signalling output, thereby influencing tumour growth, therapeutic resistance, and disease progression. Emerging evidence further highlights a complex interplay between ubiquitination, DNA damage response (DDR) pathways, and ADP-ribosylation (ADPr) signalling, collectively shaping genomic stability and treatment responsiveness in prostate cancer. This review is organized into four major themes: (i) ubiquitin-mediated regulation of AR signalling, (ii) ubiquitination and DNA damage response in AR-driven prostate cancer, (iii) crosstalk between ubiquitination, ADPr, and AR-associated signalling pathways, and (iv) therapeutic strategies targeting the UPS and AR axis. This study also discusses recent advances in targeted protein degradation, modulation of E3 ligases, inhibition of deubiquitinases, and PARP-based therapeutic approaches. These emerging insights into the interconnected regulation of ubiquitination, AR signalling, DDR pathways, and ADP-ribosylation may facilitate the development of next-generation therapeutic approaches for advanced prostate cancer.