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Inhibition of bromodomain-containing protein 4 enhances the migration of esophageal squamous cell carcinoma cells by inducing cell autophagy

BACKGROUND: Esophageal squamous cell carcinoma (ESCC), the predominant type of esophageal cancer, has a 5-year survival rate less than 20%. Although the cause of poor prognosis is the high incidence and mortality of ESCC, the high rate of metastasis after esophageal cancer surgery is the main cause...

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Autores principales: Yang, Wen-Qian, Liang, Rui, Gao, Man-Qi, Liu, Yu-Zhen, Qi, Bo, Zhao, Bao-Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Baishideng Publishing Group Inc 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9782615/
https://www.ncbi.nlm.nih.gov/pubmed/36568944
http://dx.doi.org/10.4251/wjgo.v14.i12.2340
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author Yang, Wen-Qian
Liang, Rui
Gao, Man-Qi
Liu, Yu-Zhen
Qi, Bo
Zhao, Bao-Sheng
author_facet Yang, Wen-Qian
Liang, Rui
Gao, Man-Qi
Liu, Yu-Zhen
Qi, Bo
Zhao, Bao-Sheng
author_sort Yang, Wen-Qian
collection PubMed
description BACKGROUND: Esophageal squamous cell carcinoma (ESCC), the predominant type of esophageal cancer, has a 5-year survival rate less than 20%. Although the cause of poor prognosis is the high incidence and mortality of ESCC, the high rate of metastasis after esophageal cancer surgery is the main cause of death after the surgery. Bromodomain-containing protein 4 (BRD4), an epigenetic reader of chromatin-acetylated histones in tumorigenesis and development, plays an essential role in regulating oncogene expression. BRD4 inhibition and BRD4 inhibition-based treatment can potentially suppress ESCC growth. However, the effects and mechanisms of action of BRD4 on ESCC cell migration remain unclear. AIM: To explore the effect of BRD4 on cell migration of ESCC in vitro and its possible molecular mechanism. METHODS: Human ESCC cell lines KYSE-450 and KYSE-150 were used. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay was performed to examine cell proliferation, and the transwell migration assay was conducted to test ESCC cell migration. JQ1, a BRD4 inhibitor, was applied to cells, and BRD4 siRNA 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 blotting was performed to determine the protein levels of BRD4, E-cadherin, vimentin, AMP-activated protein kinase (AMPK), and p-AMPK. RESULTS: BRD4 was either downregulated by small interfering RNA or pretreated with JQ1 in ESCC cells, leading to increased tumor migration in ESCC cells in a dose- and time-dependent manner. Inhibition of BRD4 not only significantly suppressed cell proliferation but also strongly increased cell migration by inducing epithelial-mesenchymal transition (EMT). The protein expression of vimentin was increased and E-cadherin decreased in a dose-dependent manner, subsequently promoting autophagy in KYSE-450 and KYSE-150 cells. Pretreatment with JQ1, a BRD4 inhibitor, inhibited BRD4-induced LC3-II activation and upregulated AMPK phosphorylation in a dose-dependent manner. Additionally, an increased number of autophagosomes and autolysosomes were observed in JQ1-treated ESCC cells. The autophagy inhibitor 3-methyladenine (3-MA) reversed the effects of BRD4 knockdown on ESCC cell migration and blocked JQ1-induced cell migration. 3-MA also downregulated the expression of vimentin and upregulation E-cadherin. CONCLUSION: BRD4 inhibition enhances cell migration by inducing EMT and autophagy in ESCC cells via the AMPK-modified pathway. Thus, the facilitating role on ESCC cell migration should be considered for BRD4 inhibitor clinical application to ESCC patients.
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spelling pubmed-97826152022-12-24 Inhibition of bromodomain-containing protein 4 enhances the migration of esophageal squamous cell carcinoma cells by inducing cell autophagy Yang, Wen-Qian Liang, Rui Gao, Man-Qi Liu, Yu-Zhen Qi, Bo Zhao, Bao-Sheng World J Gastrointest Oncol Basic Study BACKGROUND: Esophageal squamous cell carcinoma (ESCC), the predominant type of esophageal cancer, has a 5-year survival rate less than 20%. Although the cause of poor prognosis is the high incidence and mortality of ESCC, the high rate of metastasis after esophageal cancer surgery is the main cause of death after the surgery. Bromodomain-containing protein 4 (BRD4), an epigenetic reader of chromatin-acetylated histones in tumorigenesis and development, plays an essential role in regulating oncogene expression. BRD4 inhibition and BRD4 inhibition-based treatment can potentially suppress ESCC growth. However, the effects and mechanisms of action of BRD4 on ESCC cell migration remain unclear. AIM: To explore the effect of BRD4 on cell migration of ESCC in vitro and its possible molecular mechanism. METHODS: Human ESCC cell lines KYSE-450 and KYSE-150 were used. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay was performed to examine cell proliferation, and the transwell migration assay was conducted to test ESCC cell migration. JQ1, a BRD4 inhibitor, was applied to cells, and BRD4 siRNA 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 blotting was performed to determine the protein levels of BRD4, E-cadherin, vimentin, AMP-activated protein kinase (AMPK), and p-AMPK. RESULTS: BRD4 was either downregulated by small interfering RNA or pretreated with JQ1 in ESCC cells, leading to increased tumor migration in ESCC cells in a dose- and time-dependent manner. Inhibition of BRD4 not only significantly suppressed cell proliferation but also strongly increased cell migration by inducing epithelial-mesenchymal transition (EMT). The protein expression of vimentin was increased and E-cadherin decreased in a dose-dependent manner, subsequently promoting autophagy in KYSE-450 and KYSE-150 cells. Pretreatment with JQ1, a BRD4 inhibitor, inhibited BRD4-induced LC3-II activation and upregulated AMPK phosphorylation in a dose-dependent manner. Additionally, an increased number of autophagosomes and autolysosomes were observed in JQ1-treated ESCC cells. The autophagy inhibitor 3-methyladenine (3-MA) reversed the effects of BRD4 knockdown on ESCC cell migration and blocked JQ1-induced cell migration. 3-MA also downregulated the expression of vimentin and upregulation E-cadherin. CONCLUSION: BRD4 inhibition enhances cell migration by inducing EMT and autophagy in ESCC cells via the AMPK-modified pathway. Thus, the facilitating role on ESCC cell migration should be considered for BRD4 inhibitor clinical application to ESCC patients. Baishideng Publishing Group Inc 2022-12-15 2022-12-15 /pmc/articles/PMC9782615/ /pubmed/36568944 http://dx.doi.org/10.4251/wjgo.v14.i12.2340 Text en ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved. https://creativecommons.org/licenses/by-nc/4.0/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.
spellingShingle Basic Study
Yang, Wen-Qian
Liang, Rui
Gao, Man-Qi
Liu, Yu-Zhen
Qi, Bo
Zhao, Bao-Sheng
Inhibition of bromodomain-containing protein 4 enhances the migration of esophageal squamous cell carcinoma cells by inducing cell autophagy
title Inhibition of bromodomain-containing protein 4 enhances the migration of esophageal squamous cell carcinoma cells by inducing cell autophagy
title_full Inhibition of bromodomain-containing protein 4 enhances the migration of esophageal squamous cell carcinoma cells by inducing cell autophagy
title_fullStr Inhibition of bromodomain-containing protein 4 enhances the migration of esophageal squamous cell carcinoma cells by inducing cell autophagy
title_full_unstemmed Inhibition of bromodomain-containing protein 4 enhances the migration of esophageal squamous cell carcinoma cells by inducing cell autophagy
title_short Inhibition of bromodomain-containing protein 4 enhances the migration of esophageal squamous cell carcinoma cells by inducing cell autophagy
title_sort inhibition of bromodomain-containing protein 4 enhances the migration of esophageal squamous cell carcinoma cells by inducing cell autophagy
topic Basic Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9782615/
https://www.ncbi.nlm.nih.gov/pubmed/36568944
http://dx.doi.org/10.4251/wjgo.v14.i12.2340
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