A prostate cancer-specific super-enhancer at 1q42.3 regulates the CAPN2 and KRT19

Genetic susceptibility plays an essential role in prostate cancer (PCa) risk, while the functional mechanisms underlying several classic risk loci remain largely uncharacterized. Here, we identified a PCa specific super-enhancer within 1q42.3 locus, termed NR125945-SE, which resides within a previously reported PCa susceptibility region. Through comparative H3K27ac ChIP-seq analysis, we observed that NR125945-SE is highly active in PCa cells compared to normal controls, and this super-enhancer region is also epigenetically activated in human prostate cancer tissues. NR125945-SE contributes to PCa malignant progression. Mechanistically, integrative analysis combining RNA-seq and 4C-seq data revealed that NR125945-SE regulates the expression of CAPN2 which encoding the calpain-2 protease, and KRT19 which encoding keratin 19, through long-range chromatin interactions. Over expression of these candidate downstream targets partially rescued the transcriptional and phenotypic consequences of NR125945 deletion. Furthermore, we demonstrated that NR125945-SE activity is mediated by the cooperative binding of multiple transcription factors, including ZNF460, ETV5, and FOXK1, which physically occupy this super-enhancer. Consistently, elevated expression of CAPN2 and KRT19 was associated with poor biochemical recurrence-free survival and advanced castration-resistant prostate cancer in patient cohorts. In summary, our findings provide insights into a functional epigenetic element within a classic genetic risk locus, proposing a mechanism by which super-enhancer-mediated regulation promotes prostate cancer progression.