Histone methyltransferase EHMT2 degradation by propionate derived from Bacteroides thetaiotaomicron induced colon cancer apoptosis via epigenetic regulation of TNFAIP1

BackgroundBacteroides thetaiotaomicron (BT) is the second most commonly isolated bacterium in the human microbiome after B. fragilis and is involved in the hydrolysis of glycosidic bonds in dietary carbohydrates. Although the human microbiome has recently been shown to affect colorectal cancer (CRC) treatment, the mode of action (MOA) between the microbiome and CRC is still unclear.MethodsTo assess the colon cancer apoptosis, we performed western blot, qRT-PCR and FACS analysis using BT supernatant (Sup), sodium propionate (SP), and EHMT2 specific siRNA. Using RNA-seq analysis and ChIP-seq analysis, we identified HECTD2 (E3 ligase) and TNFAIP1 (EHMT2 target) genes. The antitumor activity of EHMT2 was determined by an in vivo xenograft model.ResultsWe selected propionate derived from BT and showed that it suppressed CRC growth by promoting proteasomal degradation of EHMT2 through HECTD2 upregulation. Moreover, downregulation of EHMT2 reduced the level of H3K9me2 on the promoter region of TNFAIP1, and subsequently, upregulation of TNFAIP1 induced apoptosis of CRC cells. Finally, we performed an in vivo study using BIX01294 to inactivate EHMT2 and observed a reduction in the tumor size of the CRC xenograft models.ConclusionsWe suggest anticancer effects of BT and EHMT2 as therapeutic targets for colon cancer treatment, and we will provide the possibility for synergistic effects of an EHMT2 inhibitor and BT in CRC treatment.*Authors share co-first authorship