Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer

Cited 39 time in scopus
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Title
Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer
Author(s)
Tae Young Ryu; Kwangho Kim; Tae-Su HanMi Ok Lee; Jinkwon Lee; Jinhyeon Choi; Kwang Bo Jung; Eun Jeong Jeong; Da Mi An; Cho-Rok JungJung Hwa LimJaeeun JungKunhyang ParkMoo-Seung Lee; M Y Kim; S J Oh; K Hur; R Hamamoto; Doo-Sang ParkDae Soo KimMi-Young SonHyun-Soo Cho
Bibliographic Citation
ISME Journal, vol. 16, no. 5, pp. 1205-1221
Publication Year
2022
Abstract
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.
ISSN
1751-7362
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/s41396-021-01119-1
Type
Article
Appears in Collections:
Division of Biomedical Research > Biotherapeutics Translational Research Center > 1. Journal Articles
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
Division of Bio Technology Innovation > Core Research Facility & Analysis Center > 1. Journal Articles
Division of Research on National Challenges > Environmental diseases research center > 1. Journal Articles
Jeonbuk Branch Institute > Biological Resource Center > 1. Journal Articles
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