Abstract
Prostate cancer is the most prevalent cancer among men worldwide and exhibits significant genetic heritability. In this study, we performed an integrative analysis combining chromatin accessibility profiling, transcriptomics, and two-stage case-control studies, alongside an unbiased phenome-wide exploration in the FinnGen cohort. This comprehensive approach identified the enhancer-associated SNP rs7077830 at chromosome 10q11 as a critical modulator of prostate cancer susceptibility. Mechanistic investigations revealed that rs7077830 exerted allele-specific enhancer activity, driving NCOA4 expression via a ZNF384-mediated enhancer-promoter interaction. CRISPR/Cas9-mediated single-nucleotide editing confirmed the direct regulatory role of rs7077830 on NCOA4 and its contribution to prostate cancer progression. Functional studies demonstrated that NCOA4 acted as a tumor suppressor by promoting ferroptosis. Furthermore, NCOA4 expression modulated sensitivity to ferroptosis-inducing agents. Strikingly, rs7077830 genotypes were directly linked to ferroptosis status in prostate cancer. These findings highlight the role of noncoding genetic variants in prostate cancer pathogenesis, provide insights into enhancer-driven ferroptosis regulation, and suggest a promising therapeutic avenue for patients with prostate cancer carrying specific rs7077830 genotypes. Significance: An enhancer mechanism mediated by a noncoding variant drives prostate cancer risk by regulating tumor suppressor expression and ferroptosis while conferring susceptibility to the potential of genotype-based precision therapeutic approaches.