Zhou J, Yang Y, Wang YL, Zhao Y, Ye WJ, Deng SY, Lang JY, Lu S. Enhancer of zeste homolog 2 contributes to apoptosis by inactivating janus kinase 2/ signal transducer and activator of transcription signaling in inflammatory bowel disease. World J Gastroenterol 2021; 27(22): 3073-3084 [PMID: 34168409 DOI: 10.3748/wjg.v27.i22.3073]
Corresponding Author of This Article
Shun Lu, MD, Chief Physician, Department of Radiation Oncology, Sichuan Cancer Hospital, No. 55 Renmin South Road, Chengdu 610041, Sichuan Province, China. lushousi90036@163.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Jun 14, 2021; 27(22): 3073-3084 Published online Jun 14, 2021. doi: 10.3748/wjg.v27.i22.3073
Enhancer of zeste homolog 2 contributes to apoptosis by inactivating janus kinase 2/ signal transducer and activator of transcription signaling in inflammatory bowel disease
Jie Zhou, Yang Yang, Yi-Ling Wang, Yue Zhao, Wen-Jing Ye, Si-Yao Deng, Jin-Yi Lang, Shun Lu
Jie Zhou, Yi-Ling Wang, Yue Zhao, Jin-Yi Lang, Shun Lu, Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu 610041, Sichuan Province, China
Yang Yang, Department of Oncology, The Third People's Hospital of Chengdu, Chengdu 255415, Sichuan Province, China
Wen-Jing Ye, Si-Yao Deng, Department of School of Medicine, University of Electronic Science and Technology of China, Chengdu 397992, Sichuan Province, China
Jin-Yi Lang, Shun Lu, Department of Radiological Protection, Radiation Oncology Key Laboratory of Sichuan Province, Chengdu 229717, Sichuan Province, China
Author contributions: Zhou J and Yang Y performed the majority of experiments and analyzed the data; Wang YL and Zhao Y performed the molecular investigations; Ye WJ and Deng SY designed and coordinated the research; Lang JY and Lu S wrote the paper; Zhou J and Yang Y contributed equally to this work.
Supported byNational Natural Science Foundation of China, No. 81900498.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Sichuan Cancer Hospital.
Institutional animal care and use committee statement: All experimental procedures with mice were performed in accordance and compliance with the regulations of the Laboratory Animal Welfare and Ethics Committee of Sichuan Cancer Hospital & Institute.
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Shun Lu, MD, Chief Physician, Department of Radiation Oncology, Sichuan Cancer Hospital, No. 55 Renmin South Road, Chengdu 610041, Sichuan Province, China. lushousi90036@163.com
Received: March 7, 2021 Peer-review started: March 7, 2021 First decision: March 27, 2021 Revised: April 9, 2021 Accepted: April 28, 2021 Article in press: April 28, 2021 Published online: June 14, 2021 Processing time: 92 Days and 16.9 Hours
ARTICLE HIGHLIGHTS
Research background
Inflammatory bowel disease (IBD) is a prevalent worldwide health problem featured by relapsing, chronic gastrointestinal inflammation. Enhancer of zeste homolog 2 (EZH2) is a critical epigenetic regulator in different pathological models, such as cancer and inflammation. However, the role of EZH2 in the IBD development is still obscure.
Research motivation
To identify the effect of EZH2 on the IBD progression and the underlying mechanism.
Research objectives
To explore the role of EZH2 in the IBD progression and the underlying mechanism.
Research methods
The IBD mouse model was conducted by adding dextran sodium sulfate (DSS) and examining the effect of EZH2 on DSS-induced colitis in the model. The function of EZH2 in regulating apoptosis and permeability was evaluated by Annexin V-FITC Apoptosis Detection Kit, transepithelial electrical resistance analysis, and Western blot analysis of related markers, including Zona occludens 1, claudin-5, and occludin, in NCM460 and fetal human colon (FHC) cells. The mechanical investigation was performed by quantitative reverse transcription-polymerase chain reaction, Western blot analysis, and chromatin immunoprecipitation assays.
Research results
The colon length was inhibited in the DSS-treated mice and was enhanced by the EZH2 depletion in the system. DSS treatment caused a decreased histological score in the mice, which was reversed by EZH2 depletion. The inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin-6, and interleukin-1β, were induced in the DSS-treated mice, in which the depletion of EZH2 could reverse this effect. Moreover, the TNF-α treatment induced the apoptosis of NCM460 and FHC cells, in which EZH2 depletion could reverse this effect in the cells. Moreover, the depletion of EZH2 attenuated permeability of colonic epithelial cells. Mechanically, the depletion of EZH2 or EZH2 inhibitor GSK343 was able to enhance the expression and the phosphorylation of JAK2 and STAT3 in the NCM460 and FHC cells. Specifically, EZH2 inactivated JAK2 expression by regulating histone H3K27me3. JAK2 inhibitor TG101348 was able to reverse EZH2 knockdown-mediated colonic epithelial cell permeability and apoptosis.
Research conclusions
EZH2 contributes to apoptosis and inflammatory response by inactivating JAK2/STAT signaling in IBD.
Research perspectives
EZH2 may be applied as a potential target for IBD therapy.
