Butyrate Inhibits Indices of Colorectal Carcinogenesis via Enhancing alpha-Ketoglutarate-Dependent DNA Demethylation of Mismatch Repair Genes

Scope: Butyrate, the fermentation end product of gut microbiota in the colon, is known for its antitumor effects, but the mechanisms remained to be defined. -ketoglutarate (-KG) mediates DNA demethylation and aberrant epigenetic modifications are associated with carcinogenesis. The objectives of this study are to evaluate the effects of butyrate on -KG mediated epigenetic modification in colorectal adenocarcinoma HT-29 and Caco-2 cells. Methods and results: Butyrate suppressed proliferation, potentiated differentiation, and induced apoptosis in both HT-29 and Caco-2 cells, associated with enhanced expression of isocitrate dehydrogenase 1 (IDH1) and pyruvate dehydrogenase. Furthermore, butyrate upregulated acetyl-CoA and -KG, concomitant with enhanced histone acetylation and DNA demethylation in the promoter of DNA mismatch repair (MMR) gene. Knocking down IDH1 abolished the positive effects of butyrate on CRC apoptosis and MMR protein expression, in conjunction with reduced -KG content. Importantly, -KG supplementation recovered the beneficial effects of butyrate in IDH1-deficient cells. Conclusion: In summary, butyrate inhibits indices of colorectal carcinogenesis in an -KG-dependent manner.