Altered patterns of hydroxymethylation regulate oncogenic pathways in pancreatic cancer. Homo sapiens

Transcriptional deregulation of oncogenic pathways is a hallmark of cancer, and can be due to epigenetic alterations. 5-hydroxymethylcytosine is a recently discovered epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC enriched loci was conducted in low-passage pancreatic cancer cell lines and primary patient-derived xenografts and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected regulatory regions of the genome, specifically overlapping with H3K4me1 enhancers. Gain of 5-hmC was correlated with upregulation of the cognate transcripts, including many oncogenic pathways implicated in pancreatic neoplasia. Specifically, BRD4 was overexpressed and acquired 5hmC at enhancer regions in majority of neoplastic samples. Functionally, acquisition of 5hmC at BRD4 promoter regulated increase in transcript expression. Furthermore, blockade of BRD4 inhibited pancreatic cancer growth in vivo. In summary, redistribution of 5-hmC and preferential enrichment at oncogenic enhancers is a novel regulatory mechanism in human cancer. Overall design: Genome-wide analysis of 5-hmC enriched loci was conducted in low-passage pancreatic cancer cell lines and primary patient-derived xenografts