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The risk SNP rs11067228 promotes prostate cancer drug resistance and neuroendocrine differentiation through 3D chromatin interactions (RNA-seq data set)

ABSTRACT: Neuroendocrine prostate cancer is an aggressive disease characterized by early metastasis, drug resistance and poor prognosis. Genome-wide association studies (GWAS) previously identified the single nucleotide polymorphism (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 active H3K27ac-enriched enhancer, and show that activity of that region affects castration-resistance and neuroendocrine differentiation in PCa cells. We identified 5 functional target genes (UGT2B15, NFASC, TBX3, SRRM4, and HSPA1A) regulated by the risk enhancer and overexpression of the RNA-splicing factor SRRM4 alone was 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 multiple genes via allele-specific long-range chromatin interactions, thereby governing PCa drug resistance and neuroendocrine differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274155 | GEO | 2026/06/30

REPOSITORIES: GEO

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Risk SNP rs11067228-mediated high-order chromatin interactions drive prostate cancer neuroendocrine differentiation through splicing factor SRRM4

Project description: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.

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