The VCPIP1‐UBE3A Deubiquitination‐Ubiquitination Cascade Contributes to Castration‐Resistant Prostate Cancer Progression

The molecular mechanisms underlying progression from metastatic hormone‐sensitive prostate cancer (mHSPC) to metastatic castration‐resistant prostate cancer (mCRPC) remain incompletely understood. Paired proteomic profiling of specimens from 10 patients identified VCPIP1 as a candidate regulator, and its clinical relevance was evaluated in an independent cohort of 128 mHSPC patients. Elevated VCPIP1 expression was independently associated with shorter CRPC‐free survival. Functional studies demonstrated that VCPIP1 promoted prostate cancer proliferation, migration, invasion, and metastasis in a deubiquitinase activity‐dependent manner. Mechanistically, VCPIP1 directly bound UBE3A and stabilized it by removing K48‐linked polyubiquitin chains at Lys711, thereby enhancing UBE3A‐mediated p53 ubiquitination and proteasomal degradation. Wild‐type UBE3A, but not its catalytically inactive C833A mutant, rescued the malignant phenotypes suppressed by VCPIP1 depletion. TP53 knockdown partially reversed these effects in TP53‐wild‐type LNCaP cells but not in TP53‐mutant DU145 cells, indicating a TP53 context‐dependent contribution of p53. VCPIP1 depletion also reduced androgen receptor expression in LNCaP cells and enhanced enzalutamide sensitivity in patient‐derived organoids. These findings identify a VCPIP1/UBE3A deubiquitination–ubiquitination cascade contributing to CRPC progression and support further investigation of VCPIP1 as a potential prognostic biomarker and therapeutic target.