Yang WQ, Liang R, Gao MQ, Liu YZ, Qi B, Zhao BS. Inhibition of bromodomain-containing protein 4 enhances the migration of esophageal squamous cell carcinoma cells by inducing cell autophagy. World J Gastrointest Oncol 2022; 14(12): 2340-2352 [PMID: 36568944 DOI: 10.4251/wjgo.v14.i12.2340]
Corresponding Author of This Article
Bao-Sheng Zhao, BMed, Chief Physician, Professor, Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, No. 88 Jiankang Road, Weihui 453100, Henan Province, China. drbszhao@xxmu.edu.cn
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/
Wen-Qian Yang, Rui Liang, Man-Qi Gao, Yu-Zhen Liu, Bo Qi, Bao-Sheng Zhao, Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
Wen-Qian Yang, Rui Liang, Man-Qi Gao, Yu-Zhen Liu, Bao-Sheng Zhao, Esophageal Cancer Institute, Xinxiang Medical University, Weihui 453100, Henan Province, China
Wen-Qian Yang, Rui Liang, Yu-Zhen Liu, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
Author contributions: Liu YZ and Zhao BS designed and coordinated the study; Yang WQ, Liang R, Gao MQ and Qi B performed the experiments, acquired and analyzed data; Yang WQ, Liu YZ and Zhao BS interpreted the data; Yang WQ, Liu YZ and Zhao BS wrote the manuscript; all authors approved the final version of the article.
Supported bythe Key Project of Science and Technology of Xinxiang, No. GG2020027; and the Health Commission of Henan Province of China, No. SBGJ202102188.
Conflict-of-interest statement: The authors declare that no conflict of interest exists in this study.
Data sharing statement: No additional data are available.
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 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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Bao-Sheng Zhao, BMed, Chief Physician, Professor, Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, No. 88 Jiankang Road, Weihui 453100, Henan Province, China. drbszhao@xxmu.edu.cn
Received: August 11, 2022 Peer-review started: August 11, 2022 First decision: October 5, 2022 Revised: October 17, 2022 Accepted: November 16, 2022 Article in press: November 16, 2022 Published online: December 15, 2022
ARTICLE HIGHLIGHTS
Research background
Bromodomain-containing protein 4 (BRD4) as a transcriptional regulator promotes tumor development. Thus, targeting of BRD4 has recently emerged as a promising anti-cancer therapeutic strategy. Although it has been reported that BRD4 inhibition repressed esophageal squamous cell carcinoma (ESCC) cell proliferation, the role of BRD4 inhibition in ESCC cell migration remains unclear.
Research motivation
To explore the role of targeting BRD4 on ESCC cell migration for developing BRD4 inhibitor combination therapies when clinical application of BRD4 inhibitor as anti-cancer therapy.
Research objectives
To explore the effect of BRD4 inhibition on ESCC cell migration and the potential mechanism.
Research methods
Human ESCC cell lines KYSE-450 and KYSE-150 were cultured. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-terazolium bromide assay was performed to examine cell proliferation and transwell assay was conducted to cell migration. JQ1 was used to inhibit BRD4 function and siBRD4 was transfected into ESCC cells to knockdown endogenous BRD4. GFP-RFP-LC3 adenovirus was infected into ESCC cells to evaluate the effect of JQ1 on autophagy. Western blot was performed to determine the protein levels of BRD4, E-cadherin, vimentin, AMP-activated protein kinase (AMPK), and p-AMPK.
Research results
JQ1 inhibited ESCC cell proliferation, but JQ1 or knockdown of BRD4 promoted ESCC cell migration as well as epithelial-mesenchymal transition (EMT). Application of JQ1 increased autophagosomes and autolysosomes in ESCC cells and enhanced level of LC3-II and AMPK phosphorylation in a dose-dependent manner. The autophagy inhibitor 3-MA blocked JQ1-induced cell migration and EMT.
Research conclusions
Inhibition of BRD4 promotes ESCC cell migration and EMT mediated by activation of autophagy.
Research perspectives
The migration-promoting effect should be carefully considered when applying JQ1 or targeting BRD4 as an anti-cancer approach. JQ1, in combination with an autophagy inhibitor, might be a new therapeutic strategy to overcome the effects of JQ1 on cancer cell migration.
