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

## TL;DR

A specific genetic variant linked to aggressive prostate cancer promotes drug resistance and a dangerous cancer type by altering gene activity through chromatin interactions.

## Contribution

The study reveals how the rs11067228 SNP influences prostate cancer progression via enhancer-mediated regulation of SRRM4.

## Key findings

- The rs11067228 SNP resides in an active enhancer region affecting castration resistance and neuroendocrine differentiation.
- SRRM4 is identified as a functional target gene influenced by rs11067228, with its overexpression inducing drug resistance and differentiation.
- The risk allele of rs11067228 enables SOX4 binding, activating gene expression and contributing to cancer progression.

## 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.