Authors
Fei Lin, Wen-Cai Zheng, Yi-Qiu Wang, Bin Lin, Yun-Zhi Lin, Dong-Ning Chen, Xiao-Dong Li, Xue-Yi Xue, Yong Wei, Ning Xu
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Oct 25, 2026. Epub Oct 25, 2026.
Abstract
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.
PMID:
42928431
Bibliographic data and abstract were imported from PubMed on 26 Oct 2026.
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