The castration-resistant prostate cancer-associated SNP rs11067228 facilitates neuroendocrine differentiation through an enhancer-mediated chromatin interaction with SRRM4

Neuroendocrine prostate cancer is an aggressive disease characterized by early metastasis, drug resistance and poor prognosis. Genome-wide association studies (GWAS) previously identified numerous single nucleotide polymorphisms (SNPs) associated with prostate cancer. SNP rs11067228 as a significant variant associated with castration-resistant metastasis (CM) in prostate cancer (PCa). However, mechanisms underlying activity of the rs11067228 risk variant remain unclear. Here, we demonstrated that risk SNP rs11067228 is located in an H3K27ac-enriched active enhancer, and that activity of that region affects castration-resistance and neuroendocrine differentiation in PCa cells. We identified the RNA-splicing factor <i>SRRM4</i> as a functional target gene as shown in both cell line and xenograft model. In addition, overexpression of <i>SRRM4</i> is sufficient to induce PCa cell drug resistance and neuroendocrine differentiation. Moreover, site-directed mutation of the rs11067228 non-risk G to the risk A allele enabled binding of the transcription factor SOX4, activating candidate target gene expression. Taken together, our findings indicated that the rs11067228-associated enhancer modulates expression of <i>SRRM4</i> via allele-specific long-range chromatin interactions, thereby governing PCa drug resistance and neuroendocrine differentiation.