Intestinal Microbiota Influences DNA Methylome and Susceptibility to Colorectal Cancer

Abstract

In a recent publication, Ansari et al. identified gut microbiota as a critical mediator of the intestinal inflammatory response through epigenetic programming of host intestinal epithelium. Exposure to the microbiota induces Ten-Eleven-Translocation (TET)-dependent hypomethylation of genomic elements regulating genes associated with inflammatory response and colorectal cancer. Here, we discuss the impact of such a discovery on the understanding of how the intestinal microbiota may contribute to epigenetic reprogramming and influence the onset of colorectal tumorigenesis. Finally, we examine the prospect of TET inhibition strategies as a therapeutic and/or preventive approach for colorectal cancer in patients afflicted by inflammatory bowel disease.

Ten-eleven translocation proteins (TETs): tumor suppressors or tumor enhancers?

“…Unlike in CCA cell lines, TET1 enhances the progestin-based chemoresistance via the upregulation of expression of the glyoxalase I gene (GLOI) mediated by its promoter hydroxymethylation in type I endometrial cancer. The TET1-mediated progestin resistance was reversed by metformin treatment through the downregulation of the GLOI expression, further suggesting the contribution of the TET1-5hmC-GLOI signaling pathway to progestin resistance in endometrial cancer [126].…”

Emerging Evidence on the Effects of Dietary Factors on the Gut Microbiome in Colorectal Cancer

“…Sfrp2 hypermethylation and subsequent downregulation are directly associated with development of hepatocellular carcinoma and CRC ( 140 ). Impaired gut microbiome activates ten-eleven translocation 3 (TET3) expression in colonocytes which induces demethylation of lamina-associated domains (LADs) leading to epigenetically programmed tumorigenesis and impaired chemotherapeutic response in CRC ( 141 , 142 ). TET enzymes have active role in inducing demethylation of 5-methylcytosine (5mC) in the CpG islands.…”

Emerging Evidence on the Effects of Dietary Factors on the Gut Microbiome in Colorectal Cancer

“…SFRP2 hypermethylation and subsequent downregulation are highly associated with development of hepatocellular carcinoma and CRC [93]. Gut bacterial dysbiosis activates ten-eleven-translocation 3 (TET3) expression in colonocytes which induces demethylation of lamina-associated domains (LADs) leading to epigenetically programmed tumorigenesis associated with impaired chemotherapeutic response in CRC [94,95]. Resveratrol, a plant based stilbenoid induces changes in the gut microbiome and is associated with an increased production of butyrate and isobutyrate producing taxa, causing release of anti-inflammatory cytokines.…”