Page 116 - ebook

[A. Biochemistry/Molecular Biology] A-58

Human microbiome-derived SCFAs coordinate a proteasomal

degradation for targeting EHMT2 in colorectal cancer

Tae Young Ryu¹, Kwangho Kim¹, Tae-Su Han¹, Jinkwon Lee¹, Mooseung Lee¹, Dae-Soo Kim¹, Mi-

Young Son¹, Hyun-Soo Cho¹*

¹Stem Cell Research Center, KRIBB, Daejeon 34141, Korea

Human microbiome play an essential role in human immune system, food digestion, and protection from harmful

bacterial by colonization in human intestine. Recently, although the human microbiome has been shown to affect
colorectal cancer (CRC) treatment, the mode of action (MOA) between the microbiome and CRC is still unclear. In

this study, we showed that propionate suppressed CRC growth by promoting proteasomal degradation of EHMT2
through HECT domain E3 ubiquitin protein ligase 2 (HECTD2) upregulation. Moreover, downregulation of EHMT2

reduced the level of H3K9me2 on the promoter region of TNFAIP1 as a novel direct target of EHMT2, and
subsequently, upregulation of TNFAIP1 induced apoptosis of CRC cells. Moreover, using culture medium of

Bacteroides thetaiotaomicron, we confirmed EHMT2 down-regulation via up-regulation of HECTD2, and up-
regulation of TNFAIP1 expression by exchange of H3K9 di-methylation. 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. Thus we
suggest anticancer effects of propionate and EHMT2 as therapeutic targets for colon cancer treatment, and we will

provide the possibility for synergistic effects of an EHMT2 inhibitor and microbiome in CRC treatment.