Epithelial Alternative Polyadenylation Identifies Hepatoma-Derived Growth Factor as a Genetically Supported Candidate in Prostate Cancer

Background/Objectives: Alternative polyadenylation (APA) remodels 3′ untranslated regions and may affect transcript stability, translational efficiency, and protein output without proportional changes in total mRNA abundance. Its tumor-epithelial landscape and protein-level genetic relevance in prostate cancer remain incompletely defined. Methods: We compared tumor and luminal epithelial cells across two patient-derived single-cell RNA-sequencing cohorts and identified recurrent 3′UTR shortening events. These genes were integrated with cis-protein quantitative trait locus-based Mendelian randomization, outcome replication, and colocalization analyses of prostate cancer risk. Prioritized candidates were further assessed using transcriptomic, proteomic, histological, computational perturbation, and structure-based screening analyses. Results: Tumor epithelial cells showed widespread 3′UTR shortening, with 1066 shortened genes shared across cohorts. Integrating recurrent epithelial APA shortening with protein-genetic evidence prioritized hepatoma-derived growth factor (HDGF). Genetically proxied higher plasma HDGF was associated with higher prostate cancer odds across datasets, although the strength of genetic support was sensitive to instrument correlation and colocalization assumptions. HDGF also showed preferential proximal poly(A)-site use and increased RNA and protein abundance in prostate tumors, and higher expression was associated with shorter biochemical recurrence-free survival. Conclusions: HDGF is an APA-associated candidate supported by complementary protein-genetic and tissue-level evidence in prostate cancer.