Abstract
Polyubiquitination plays a critical role in tumor biology, yet its significance in prostate cancer remains incompletely understood. Here, we investigated the expression and function of SOCS-box E3 ligases in prostate cancer. Analysis of TCGA data revealed WSB1 overexpression, which correlated with advanced pathological stage, high Gleason score, and poor prognosis. Functional assays demonstrated that WSB1 knockdown suppressed prostate cancer cell proliferation, colony formation, and migration in vitro, and inhibited tumor growth and Ki67 expression in vivo. Mechanistically, mass spectrometry and co-immunoprecipitation identified ISOC2 as a key WSB1 interactor. WSB1 stabilized ISOC2 by promoting its interaction with the deubiquitinase OTUD4, thereby preventing ISOC2 degradation via the ubiquitin-proteasome pathway. Silencing either ISOC2 or OTUD4 phenocopied the tumor-suppressive effects of WSB1 ablation. Importantly, disruption of the WSB1/OTUD4/ISOC2 axis upregulated P16INK4a expression, and co-silencing of P16INK4a partially restored tumorigenic properties. Our findings unveil a novel WSB1/OTUD4/ISOC2 signaling network that drives prostate cancer progression by modulating ubiquitin signaling and repressing P16INK4a, positioning WSB1 as a promising therapeutic target.