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Human microbiome derived SCFAs coordinates a proteasomal

degradation for targeting EHMT2 in colorectal cancer

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Tae Young Ryu , Kwangho Kim , Tae-Su Han , Jinkwon Lee , Mooseung Lee , Dae-Soo Kim , Mi-Young Son , Hyun-Soo Cho 1, 2
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Korea Research Institute of Bioscience and Biotechnology (KRIBB), KRIBB School of Bioscience, Korea University of Science and Technology (UST)

ABSTRACT Fig. 4 Knockdown of EHMT2 is involved in CRC apoptosis. Fig. 8 Synergistic effect of SP and BIX01294 in the 3D

spheroid model.
The human microbiome plays an essential role in the human

immune system, food digestion, and protection from harmful

bacteria by colonizing the human intestine. Recently, although the

human microbiome affects colorectal cancer (CRC) treatment, the

mode of action between the microbiome and CRC remains unclear.

This study showed that propionate suppressed CRC growth by

promoting the proteasomal degradation of euchromatic histone-

lysine N-methyltransferase 2 (EHMT2) through HECT domain E3

ubiquitin protein ligase 2 (HECTD2) upregulation. In addition,

EHMT2 downregulation reduced the H3K9me2 level on the

promoter region of tumor necrosis factor α-induced protein 1

(TNFAIP1) as a novel direct target of EHMT2. Subsequently,

TNFAIP1 upregulation induced the apoptosis of CRC cells.

Furthermore, using Bacteroides thetaiotaomicron culture medium,

we confirmed EHMT2 downregulation via upregulation of HECTD2

and TNFAIP1 upregulation. Finally, we observed the synergistic

effect of propionate and an EHMT2 inhibitor (BIX01294) in 3D

spheroid culture models. Thus, we suggest the anticancer effects

of propionate and EHMT2 as therapeutic targets for colon cancer

treatment and may provide the possibility for the synergistic effects

of an EHMT2 inhibitor and microbiome in CRC treatment.

Fig. 1 Propionate suppresses the cell growth of HCT116 and

LS174T cells via cell apoptosis.

Fig. 5 Negative regulation of TNFAIP1 by EHMT2 induces CRC

apoptosis.

SUMARRY

Fig. 2 EHMT2 is a target for propionate-induced cell apoptosis in

colon cancer.

Fig. 6 The supernatant of BT culture medium suppresses the

growth of HCT116 and LS174T cells via propionate-induced

apoptosis.

In this study, we demonstrated the anticancer effect of propionate at the epigenetic

level. Propionate treatment upregulated HECT domain E3 ubiquitin protein ligase 2

(HECTD2) expression to promote the proteasomal degradation of EHMT2 via

posttranslational modifications. Subsequently, EHMT2 downregulation by propionate

induced tumor necrosis factor α-induced protein 1 (TNFAIP1) expression by

reducing H3K9me2 levels to promote colon cancer apoptosis. Additionally, we

confirmed this mechanism using Bacteroides thetaiotaomicron (BT) culture medium.

Finally, we identified EHMT2 as a therapeutic target for colon cancer treatment with

propionate.

Fig. 3 SP treatment induces HECTD2 expression for EHMT2

degradation Acknowledgments

This work was supported by a grant from the Technology Innovation

Fig. 7 EHMT2 is a therapeutic target for CRC. Program (No. 20008777) funded by the Ministry of Trade, Industry &

Energy (MOTIE, Korea), the National Research Foundation of Korea (NRF)

grant funded by the Ministry of Science, ICT, and Future Planning (NRF-

2020R1A2B5B01002028, NRF-2018M3A9H3023077/ NRF-

2021M3A9H3016046), and supported by the Korean Fund for Regenerative

Medicine (KFRM) grant funded by the Korea government (the Ministry of

Science and ICT, the Ministry of Health & Welfare, 21A0404L1), and the

KRIBB Research Initiative Program. The funders had no role in the study

design, data collection or analysis, decision to publish, or preparation of the

manuscript.