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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 Apcmin/+ 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 …
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