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

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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.

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Most cited references 46

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From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites.

Ara Koh, Filipe De Vadder, Petia Kovatcheva-Datchary … (2016)

A compelling set of links between the composition of the gut microbiota, the host diet, and host physiology has emerged. Do these links reflect cause-and-effect relationships, and what might be their mechanistic basis? A growing body of work implicates microbially produced metabolites as crucial executors of diet-based microbial influence on the host. Here, we will review data supporting the diverse functional roles carried out by a major class of bacterial metabolites, the short-chain fatty acids (SCFAs). SCFAs can directly activate G-coupled-receptors, inhibit histone deacetylases, and serve as energy substrates. They thus affect various physiological processes and may contribute to health and disease.

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Human organoids: model systems for human biology and medicine

Jihoon Kim, Bon-Kyoung Koo, Juergen A. Knoblich (2020)

The historical reliance of biological research on the use of animal models has sometimes made it challenging to address questions that are specific to the understanding of human biology and disease. But with the advent of human organoids — which are stem cell-derived 3D culture systems — it is now possible to re-create the architecture and physiology of human organs in remarkable detail. Human organoids provide unique opportunities for the study of human disease and complement animal models. Human organoids have been used to study infectious diseases, genetic disorders and cancers through the genetic engineering of human stem cells, as well as directly when organoids are generated from patient biopsy samples. This Review discusses the applications, advantages and disadvantages of human organoids as models of development and disease and outlines the challenges that have to be overcome for organoids to be able to substantially reduce the need for animal experiments.

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The role of short-chain fatty acids in health and disease.

Jian Tan, Craig McKenzie, Maria Potamitis … (2014)

There is now an abundance of evidence to show that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and the development of disease. SCFAs are a subset of fatty acids that are produced by the gut microbiota during the fermentation of partially and nondigestible polysaccharides. The highest levels of SCFAs are found in the proximal colon, where they are used locally by enterocytes or transported across the gut epithelium into the bloodstream. Two major SCFA signaling mechanisms have been identified, inhibition of histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs). Since HDACs regulate gene expression, inhibition of HDACs has a vast array of downstream consequences. Our understanding of SCFA-mediated inhibition of HDACs is still in its infancy. GPCRs, particularly GPR43, GPR41, and GPR109A, have been identified as receptors for SCFAs. Studies have implicated a major role for these GPCRs in the regulation of metabolism, inflammation, and disease. SCFAs have been shown to alter chemotaxis and phagocytosis; induce reactive oxygen species (ROS); change cell proliferation and function; have anti-inflammatory, antitumorigenic, and antimicrobial effects; and alter gut integrity. These findings highlight the role of SCFAs as a major player in maintenance of gut and immune homeostasis. Given the vast effects of SCFAs, and that their levels are regulated by diet, they provide a new basis to explain the increased prevalence of inflammatory disease in Westernized countries, as highlighted in this chapter.

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Author and article information

Contributors

Doo-Sang Park:

ORCID: http://orcid.org/0000-0003-4528-6789

dspark@kribb.re.kr

Dae-Soo Kim:

ORCID: http://orcid.org/0000-0002-4999-1613

kds2465@kribb.re.kr

Mi-Young Son:

ORCID: http://orcid.org/0000-0001-7590-8812

myson@kribb.re.kr

Hyun-Soo Cho:

ORCID: http://orcid.org/0000-0002-8242-9390

chohs@kribb.re.kr

Journal

Journal ID (nlm-ta): ISME J

Journal ID (iso-abbrev): ISME J

Title: The ISME Journal

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1751-7362

ISSN (Electronic): 1751-7370

Publication date (Electronic): 1 January 2022

Publication date PMC-release: 1 January 2022

Publication date (Print): May 2022

Volume: 16

Issue: 5

Pages: 1205-1221

Affiliations

[1 ]GRID grid.249967.7, ISNI 0000 0004 0636 3099, Korea Research Institute of Bioscience and Biotechnology, ; Daejeon, 34141 Republic of Korea

[2 ]GRID grid.37172.30, ISNI 0000 0001 2292 0500, Department of Biological Sciences, , Korea Advanced Institute of Science and Technology (KAIST), ; Daejeon, 34141 Republic of Korea

[3 ]GRID grid.412786.e, ISNI 0000 0004 1791 8264, Korea University of Science and Technology, ; Daejeon, 34113 Republic of Korea

[4 ]GRID grid.267370.7, ISNI 0000 0004 0533 4667, Asan Institute for Life Sciences, Asan Medical Center and Department of Convergence Medicine, College of Medicine, , University of Ulsan, ; Seoul, 05505 Republic of Korea

[5 ]GRID grid.258803.4, ISNI 0000 0001 0661 1556, Department of Biochemistry and Cell biology, School of Medicine, , Kyungpook National University, ; Daegu, 41944 Republic of Korea

[6 ]GRID grid.272242.3, ISNI 0000 0001 2168 5385, Division of Molecular Modification and Cancer Biology, , National Cancer Center, ; Tokyo, 104-0045 Japan

Author information

Doo-Sang Park http://orcid.org/0000-0003-4528-6789

Dae-Soo Kim http://orcid.org/0000-0002-4999-1613

Mi-Young Son http://orcid.org/0000-0001-7590-8812

Hyun-Soo Cho http://orcid.org/0000-0002-8242-9390

Article

Publisher ID: 1119

DOI: 10.1038/s41396-021-01119-1

PMC ID: 9038766

PubMed ID: 34972816

SO-VID: 6159c372-8e98-4de6-92f3-86a61c600740

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 15 September 2020

Date revision received : 8 September 2021

Date accepted : 14 September 2021

Custom metadata

ScienceOpen disciplines: Microbiology & Virology

Keywords: colorectal cancer,transcriptomics,functional genomics

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ScienceOpen disciplines: Microbiology & Virology

Keywords: colorectal cancer, transcriptomics, functional genomics

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

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Microbial Genomics

Most cited references 46

From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites.

Human organoids: model systems for human biology and medicine

The role of short-chain fatty acids in health and disease.

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Cited by 25

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