Abstract

Genetic and nonmutational epigenetic alterations are cancer hallmark characteristics. However, the role of inherited cancer predisposition alleles in co-opting lineage factor epigenetic reprogramming and contributing to tumor progression remains elusive. Here the FinnGen cohort phenome-wide analysis, along with recent multiple genome-wide association studies, has consistently identified the rs339331-RFX6/6q22 locus associated with prostate cancer (PCa) risk across diverse populations. We uncover that rs339331 resides at a reprogrammed androgen receptor (AR) binding site in PCa tumors, with the T risk allele enhancing AR chromatin occupancy under androgen signaling. We establish that RFX6 is an AR-regulated gene, intricately linked with rs339331, exhibiting synergistic prognostic value for PCa recurrence and metastasis. Through comprehensive in vitro and in vivo studies, we establish the oncogenic functions of RFX6 in promoting PCa cell proliferation and metastasis. Mechanistically, RFX6 upregulates transcription factor HOXA10 that profoundly correlates with adverse PCa outcomes and is pivotal in RFX6-mediated PCa progression, facilitating the epithelial-mesenchymal transition (EMT) process and modulating the TGF{beta}/SMAD signaling axis. Clinically, HOXA10 elevation is associated with increased EMT scores, tumor advancement and PCa recurrence. Remarkably, reducing RFX6 expression restores responsiveness of enzalutamide-resistant PCa cells and tumors to treatment. Our study highlights an interplay of disrupted genetic and epigenetic mechanisms converging on prostate lineage AR signaling, resulting in abnormal expression of RFX6 conferring PCa pathogenesis and enzalutamide resistance.