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人肠道微生物组衍生的丙酸盐通过 HECTD2 的上调协调蛋白酶体降解，以靶向结直肠癌中的 EHMT2。

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

机构信息

Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.

Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.

出版信息

ISME J. 2022 May;16(5):1205-1221. doi: 10.1038/s41396-021-01119-1. Epub 2022 Jan 1.

DOI:10.1038/s41396-021-01119-1
PMID:34972816
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9038766/
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.

摘要

人类微生物组在人类免疫系统、食物消化以及通过定植人类肠道来保护免受有害细菌方面发挥着重要作用。最近，尽管人类微生物组影响结直肠癌（CRC）的治疗，但微生物组与 CRC 之间的作用模式仍不清楚。本研究表明，丙酸盐通过上调 HECT 结构域 E3 泛素蛋白连接酶 2（HECTD2）来促进染色质组蛋白赖氨酸 N-甲基转移酶 2（EHMT2）的蛋白酶体降解，从而抑制 CRC 生长。此外，EHMT2 的下调降低了肿瘤坏死因子α诱导蛋白 1（TNFAIP1）启动子区域的 H3K9me2 水平，EHMT2 是 TNFAIP1 的一个新的直接靶标。随后，TNFAIP1 的上调诱导 CRC 细胞凋亡。此外，通过上调 HECTD2 和 TNFAIP1 的上调，我们使用拟杆菌属培养物培养基证实了 EHMT2 的下调。最后，我们在 3D 球体培养模型中观察到丙酸盐和 EHMT2 抑制剂（BIX01294）的协同作用。因此，我们建议丙酸盐和 EHMT2 的抗癌作用作为结肠癌治疗的治疗靶点，并可能为 EHMT2 抑制剂和微生物组在 CRC 治疗中的协同作用提供可能性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/8ab4f48a2e02/41396_2021_1119_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/f67e2b60b04d/41396_2021_1119_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/52edc4b067a2/41396_2021_1119_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/7ad06432dc9e/41396_2021_1119_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/a93acedb8df5/41396_2021_1119_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/ec6607427b49/41396_2021_1119_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/d529d1756e87/41396_2021_1119_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/8e10666337fb/41396_2021_1119_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/2dc98b42503c/41396_2021_1119_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/8ab4f48a2e02/41396_2021_1119_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/f67e2b60b04d/41396_2021_1119_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/52edc4b067a2/41396_2021_1119_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/7ad06432dc9e/41396_2021_1119_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/a93acedb8df5/41396_2021_1119_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/ec6607427b49/41396_2021_1119_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/d529d1756e87/41396_2021_1119_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/8e10666337fb/41396_2021_1119_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/2dc98b42503c/41396_2021_1119_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0476/9038766/8ab4f48a2e02/41396_2021_1119_Fig9_HTML.jpg

相似文献

[1]
Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer.

ISME J. 2022-5

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[5]
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引用本文的文献

[1]
Apoptosis-Inducing Effects of DS0709 in Colorectal Cancer.

J Microbiol Biotechnol. 2025-8-15

[2]
Metabolic interactions: how gut microbial metabolites influence colorectal cancer.

Front Microbiol. 2025-7-23

[3]
Lipid metabolic reprogramming in colorectal cancer: mechanisms and therapeutic strategies.

Front Immunol. 2025-7-11

[4]
Theabrownin combined with zearalenone suppresses colitis-associated colorectal cancer by inhibiting PI3K/AKT pathway and enhancing microbial propionate production.

Sci Rep. 2025-7-21

[5]
Microbial diagnostic features identified across populations possess potential antitumor properties in breast cancer.

mSystems. 2025-7-22

[6]
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Int J Med Sci. 2025-5-16

[7]
One of the Short-Chain Fatty Acids (SCFAs), Sodium Propionate, Can Reduce the Dosage of Sishen Pill in Regulating the Intestinal Microbiota in Diarrhea with Kidney-Yang Deficiency Syndrome.

J Inflamm Res. 2025-6-5

[8]
Enhancement of 5-fluorouracil efficacy in colorectal cancer cells through thymidylate synthase inhibition by sodium propionate.

In Vitro Cell Dev Biol Anim. 2025-6-6

[9]
Implications of gut microbiota-mediated epigenetic modifications in intestinal diseases.

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[10]
Gut dysbiosis from high-salt diet promotes glioma via propionate-mediated TGF-β activation.

J Exp Med. 2025-8-4

本文引用的文献

[1]
Downregulation of PRMT1, a histone arginine methyltransferase, by sodium propionate induces cell apoptosis in colon cancer.

Oncol Rep. 2018-12-18

[2]
The novel prognostic marker, EHMT2, is involved in cell proliferation via HSPD1 regulation in breast cancer.

Int J Oncol. 2019-1

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