Summary data-based mendelian randomization and single-cell RNA sequencing analyses identify key genes associated with ubiquitination in prostate cancer

Background: Studies demonstrate that ubiquitination significantly contributes to tumor modulation by governing cellular viability, multiplication, and specialization. Nevertheless, the exact functions of ubiquitination-related genes (URGs) within prostate cancer (PCa) pathogenesis have yet to be fully elucidated. This investigation focused on detecting pivotal genetic markers correlated with URGs in PCa, potentially enabling novel directions for precision-based treatment development. Methods: PCa-associated datasets were acquired from publicly accessible repositories. Critical cellular subtypes were first delineated using scRNA-seq analytical methods. Differentially expressed genes (DEGs) within these prioritized cell populations were subsequently screened and intersected with ubiquitination-associated genetic markers to identify potential candidates. Causal inference was performed through Summary data-based Mendelian randomization (SMR) complemented by MR methodologies to discern genes exhibiting robust causal links with PCa progression. Mechanistic exploration further incorporated colocalization assessments, pharmacological target forecasting, in silico docking simulations, and temporal trajectory modeling to decode the biological pathways implicated in PCa pathogenesis. Results: In PCa, primary cellular components were established as T lymphocytes and epithelial cells, with POLI and TRIM8 emerging as principal genetic elements linked to pathogenesis. Both genetic markers demonstrated protective characteristics against PCa development through combined eQTL and mQTL analyses, exhibiting significant odds ratios (POLI: OR=0.9385, 95% CI=0.8982-0.9806, P=0.0046; TRIM8: OR=0.8648, 95% CI=0.8118-0.9213, P<0.001). Colocalization assessments confirmed substantial associations between these genetic loci and disease pathophysiology (posterior probability >0.6). Pharmacological predictions identified selegiline hydrochloride as a therapeutic candidate, demonstrating promising binding affinity (-11.3 kcal/mol) with POLI. Developmental trajectory mapping of epithelial and T cell lineages revealed distinct cellular differentiation pathways, categorized into 11 and 5 maturation phases accompanied by 14 and 11 phenotypic subtypes respectively. TRIM8 exhibited stage-specific regulatory functions during cellular maturation processes, displaying differential expression profiles across developmental sequences. Conclusions: This investigation revealed POLI and TRIM8 as critical molecular targets in PCa pathogenesis, providing crucial molecular insights for advancing precision therapeutic strategies in prostate cancer management.