Anoikis resistance is a critical factor enabling the colonization of distant organs by solid tumor cells, including prostate cancer (PCa), and serves as a key mechanism underlying the transition from localized to metastatic PCa. Ubiquitin C-terminal hydrolase L5 (UCHL5) functions as an oncogene in various cancers, yet its role in PCa metastasis remains poorly understood. UCHL5 expression was assessed in PCa clinical samples via immunohistochemistry, Western blotting, and public database analysis. The biological functions of UCHL5 in proliferation, migration, invasion, and anoikis resistance were evaluated both in vitro and in vivo . Molecular mechanisms were explored using co-immunoprecipitation coupled with mass spectrometry, immunofluorescence, dual-luciferase reporter assays, and Western blotting analysis of key signaling pathways. UCHL5 overexpression in PCa tissues correlated with an aggressive tumor phenotype and poor patient prognosis. Functionally, UCHL5 enhanced PCa cell proliferation, metastasis, and anoikis resistance in both in vitro and in vivo models. Mechanistically, UCHL5 interacted directly with HSPA5, stabilizing it by cleaving its K48-linked polyubiquitin chains, thereby reducing endoplasmic reticulum stress and inhibiting endoplasmic reticulum stress-induced anoikis. Furthermore, the UCHL5–HSPA5 axis activated the Wnt/β-catenin signaling pathway, leading to up-regulation of the oncogene MYC. Notably, MYC transcriptionally up-regulated UCHL5 expression, establishing a positive feedback loop that drives PCa progression and metastasis. This study uncovers a novel UCHL5–HSPA5–MYC feedback loop that promotes PCa metastasis by enhancing anoikis resistance through the mitigation of endoplasmic reticulum stress. Targeting this axis may provide an effective therapeutic strategy for metastatic PCa.
Wang et al. (Fri,) studied this question.