Work

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

Year: 2026

Type: article

Abstract: 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 SRRM4 as a functional target gene as shown in both cell line and xenograft model.In addition, overexpression of SRRM4 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 SRRM4 via allele-specific long-range chromatin interactions, thereby governing PCa drug resistance and neuroendocrine differentiation.

Source: International Journal of Biological Sciences

DOI: 10.7150/ijbs.124731