TRIM2 suppresses prostate cancer progression by promoting ubiquitin-mediated degradation of DTNBP1.

Abstract

Objective/background: Prostate cancer is the most commonly diagnosed malignancy in men worldwide, with high mortality rates and frequent metastasis at initial diagnosis, underscoring the need to elucidate its molecular mechanisms. TRIM2, an E3 ubiquitin ligase, plays critical roles in several cancers, but its function in prostate cancer remains unclear. This study aimed to investigate the expression, biological function, and clinical significance of TRIM2 in PCa progression.

Methods: TRIM2 expression was analyzed using TCGA, GTEx, and GEO datasets, and validated in PCa and BPH tissues via qRT-PCR, western blot, and immunohistochemistry. Functional assays (CCK-8, wound healing, Transwell, flow cytometry) were performed in DU145 and PC-3 cells with TRIM2 overexpression or knockdown, and xenograft models assessed tumorigenicity in vivo. Proteomic sequencing combined with database prediction (UbiBrowser, BioGRID) identified DTNBP1 as a downstream substrate, confirmed by co-immunoprecipitation, ubiquitination assays, and cycloheximide chase. Drug sensitivity was evaluated using the GDSC database and molecular docking.

Results: TRIM2 was significantly downregulated in PCa tissues, with the lowest levels observed in advanced and castration-resistant cases, and its reduced expression independently predicted worse progression-free interval. ROC analysis demonstrated that TRIM2 effectively discriminated localized from advanced/CRPC disease. TRIM2 overexpression significantly suppressed malignant behaviors in vivo and vitro. Mechanistically, TRIM2 directly interacted with DTNBP1 and promoted its ubiquitin-proteasome-mediated degradation. Drug sensitivity analysis and molecular docking revealed that TRIM2 expression serves as a predictor of PCa cell sensitivity to clinically relevant agents, including olaparib and navitoclax.

Conclusion: Our findings establish the TRIM2-DTNBP1 axis as a key driver of PCa progression and position TRIM2 as a promising prognostic biomarker and a potential predictive indicator for guiding molecularly targeted therapies in advanced PCa.