The Deubiquitinating Enzyme USP46 Abolishes Cell Survival of Prostate Cancer via Enhancing BECN1‐Dependent Autophagy

Ubiquitin-specific peptidase 46 (USP46) is frequently underexpressed in several cancers. Its involvement and functional role in prostate cancer, however, are not well understood. This research focused on exploring how USP46 may suppress prostate cancer and its underlying mechanisms. USP46 mRNA levels in clinical prostate cancer samples were analyzed using the online The University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) database. The expression of USP46 mRNA and protein was analyzed using RT-PCR and immunoblotting techniques. Cell proliferation, colony formation assays, and tumor growth curves were assessed by Cell Counting Kit-8 assay, crystal violet staining, and xenograft model, respectively. USP46's interaction with beclin 1 (BECN1) was evaluated using immunoprecipitation assays, whereas BECN1 knockdown was performed with siRNA. USP46 mRNA expression was significantly lower in prostate cancer cells compared to that in normal cells. Overexpression of USP46 significantly reduced cell proliferation, as shown by decreased cell viability and fewer colonies. Mechanistic studies demonstrated that USP46 interacted with and stabilized BECN1, supported by findings showing that USP46 overexpression increased BECN1 levels and delayed its degradation in prostate cancer cells treated with cycloheximide. Additionally, knockdown of BECN1 and inhibition of autophagy partially restored cell proliferation in USP46-overexpressing cells. USP46 interacts with and stabilizes BECN1, promoting autophagy and thereby suppressing prostate cancer cell proliferation. In conclusion, the current findings demonstrate that USP46 abolishes cell survival of prostate cancer via enhancing BECN1-dependent autophagy.