Linking inflammation to epigenetics in intestinal carcinogenesis

▶ Xia D, Wang D, Kim SH, et al. Prostaglandin E₂ promotes intestinal tumour growth via DNA methylation. Nat Med 2012;18:224–6. doi:10.1038/nm.2608

Inflammation is associated with aberrant DNA methylation which, in turn, is implicated in the pathogenesis of several human cancers. However, it remains unclear what mechanisms drive inflammation-related DNA methylation. Furthermore, the processes that link inflammation to cellular transformation and tumour evolution remain obscure. A recent report by Xia and colleagues sheds light on a link between inflammation, epigenetic change and carcinogenesis. Using quantitative PCR, a positive correlation was observed between PTGS2 (cyclooxygenase 2) and PGE₂ (prostaglandin E₂) expression, and expression of DNA methyltransferases (DNMT1 and DNMT3B) in human colorectal cancer. Additionally, in the colon cancer-derived HT-29 cell line, celecoxib-induced downregulation of DNMT expression could be overcome by exposure to PGE₂. The authors examined CpG island hypermethylation in the LS174T cell line and found that PGE₂ enhanced DNA methylation at several loci, including the MGMT and MLH1 promoters. Knockdown of DNMT1 or DNMT3B by short hairpin RNAs attenuated PGE₂-induced downregulation of MGMT and MLH1. These data suggest that PGE₂ promotes DNMT-dependent epigenetic gene silencing of tumour suppressor genes. The authors validated these findings in the Apc^min/+ mouse. Mice treated with PGE₂ experienced accelerated tumourigenesis and demonstrated increased DNMT1 and DNMT3B protein levels in colonic tumours. In addition, treatment with PGE₂ promoted locus-specific promoter hypermethylation. Treatment with celecoxib and a DNA methylation inhibitor (5-Aza-dC) resulted in a synergistic reduction in tumour burden. The tumour inhibitory effect of celecoxib on small intestinal adenomas could be overcome by PGE₂, suggesting that the effect of celecoxib is mediated through modulation of PGE₂ levels. Collectively, the findings suggest that PGE₂ promotes intestinal …