IFN-γ activates p300 to over-ride silencing effects of DNA methylation to activate GPR109A and SLC5A8 transcription (P2105)

Abstract

Abstract Short-chain fatty acids, metabolites produced by colonic microbiota from fermentation of dietary fiber, act as anti-inflammatory agents in the intestinal tract to suppress inflammation-mediated diseases such as inflammatory bowel disease and colorectal cancer. GPR109A and SLC5A8, receptor and transporter, respectively, for short chain fatty acids, are often silenced in human colon carcinoma cells. We demonstrated that the GPR109A and SLC5A8 promoter DNA is hypermethylated in human colon carcinoma cells in vitro and in vivo. Strikingly, IFN-γ, a cytokine secreted by activated cytotoxic T lymphocytes, effectively activated GPR109A and SLC5A8 transcription without altering their promoter DNA methylation levels. Analysis of the IFN-γ signaling pathways indicated that IFN-γ-activated pSTAT1 binds to the promoter of immediate early target gene p300 to rapidly activate p300 transcription. p300 then binds to the GPR109A and SLC5A8 promoters and induces chromatin hyperacetylation, resulting in chromatin remodeling in the hypermethylated GPR109A and SLC5A8 promoter regions. pSTAT1 then directly binds to the remodeled but still hypermethylated GPR109A and SLC5A8 promoters to activate transcription of secondary response genes GPR109A and SLC5A8. Taken together, our data suggest that the host immune system might use IFN-γ to counteract DNA methylation-mediated silencing of tumor suppressor genes as a mechanism to suppress tumor development.