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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Trichostatin A augments cell migration and epithelial-mesenchymal transition in esophageal squamous cell carcinoma through BRD4/c-Myc endoplasmic reticulum-stress pathway
Yan-Min Chen, Wen-Qian Yang, Ying-Ying Fan, Zhi Chen, Yu-Zhen Liu, Bao-Sheng Zhao
Yan-Min Chen, Wen-Qian Yang, Yu-Zhen Liu, Bao-Sheng Zhao, Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
Yan-Min Chen, Department of Oncology, The First Affiliated Hospital of Henan Polytechnic University, Jiaozuo 454000, Henan Province, China
Wen-Qian Yang, Yu-Zhen Liu, Bao-Sheng Zhao, Henan Medical Science Key Laboratory of Esophageal Cancer Metastasis Translational Medicine, Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
Wen-Qian Yang, Yu-Zhen Liu, Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
Ying-Ying Fan, Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
Zhi Chen, Department of Anesthesiology, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453100, Henan Province, China
Co-first authors: Yan-Min Chen and Wen-Qian Yang.
Co-corresponding authors: Yu-Zhen Liu and Bao-Sheng Zhao.
Author contributions: All authors contributed to the study’s conception and design; Chen YM, Liu YZ, and Zhao BS made contributions to the conception and design of this study; Chen YM, Yang WQ and Chen Z conducted experiments; Fan YY, Yang WQ and Zhao BS were responsible for clinical sample collection; Chen Y and Yang WQ participated in data analysis; Chen YM, Liu YZ, Yang WQ and Zhao BS wrote the manuscript.
Supported by the Henan Province Science and Technology Development Plan, No. 242102311124; Key Medical Scientific and Technological Project of Henan Province, No. SBGJ202102188; Henan Provincial Medical Science and Technology Project, No. LHGJ20221012; and Fundamental Research Funds for the Universities of Henan Province, No. NSFRF240308.
Institutional review board statement: This study was reviewed and approved by the First Affiliated Hospital of Xinxiang Medical University Institutional Review Board (Approval No. EC-024-559).
Institutional animal care and use committee statement: This study does not involve any animal experimentation.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
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 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:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Bao-Sheng Zhao, MD, 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: November 25, 2024
Revised: January 9, 2025
Accepted: February 14, 2025
Published online: March 21, 2025
Processing time: 111 Days and 1.3 Hours
BACKGROUND
The causes of death in patients with advanced esophageal cancer are multifactorial, with tumor metastasis being one of the important factors. Histone acetylation promotes the migration of esophageal squamous cell carcinoma (ESCC) cells, while the histone deacetylase inhibitor (HDACi) shows complex effects on tumor functions.
AIM
To comprehensively elucidate the impact and molecular mechanisms of trichostatin A (TSA), an HDACi, on cell migration in ESCC through bromodomain-containing protein (BRD4)/cellular myelocytomatosis oncogene (c-Myc)/endoplasmic reticulum (ER)-stress.
METHODS
The effects of TSA on ESCC cell lines Eca109 and EC9706 migration were evaluated using Transwell assays, with small interfering transfection and pathway-specific inhibitors to elucidate underlying mechanisms. The mRNA levels involved were examined by quantitative real-time polymerase chain reaction. Protein levels of acetylated histones H3 (acH3) and acetylated histones H4, BRD4, c-Myc, as well as markers of ER stress and epithelial-mesenchymal transition (EMT), were analyzed using western blot. Additionally, this method was also used to examine acH3 levels in esophageal cancer tissues and adjacent tissues. Patient outcomes were subsequently tracked to identify prognostic indicators using Log-Rank tests and Cox multivariate analysis.
RESULTS
TSA promoted the migration of ESCC cells by stimulating the EMT process. TSA-mediated histone acetylation facilitated the recruitment of BRD4, a bromodomain-containing protein, triggering the expression of c-Myc. This cascade induced ER stress and enhanced EMT in ESCC cells. To further elucidate the underlying mechanism, we employed various interventions including the ER stress inhibitor 4-phenylbutyric acid, knockdown of c-Myc and BRD4 expression, and utilization of the BRD4 inhibitor carboxylic acid as well as the inhibitor of TSA 1. Mechanistically, these studies revealed that TSA-mediated histone acetylation facilitated the recruitment of BRD4, which in turn triggered the expression of c-Myc. This sequential activation induced ER stress and subsequently enhanced EMT, thereby promoting the migration of ESCC cells. Additionally, we examined histone acetylation levels in specimens from 43 patients with ESCC, including both tumor tissues and paired adjacent tissues. Statistical analysis unveiled a negative correlation between the level of histone acetylation and the long-term prognosis of patients with ESCC.
CONCLUSION
TSA promoted ESCC cell migration through the BRD4/c-Myc/ER stress pathway. Moreover, elevated histone acetylation in ESCC tissues correlated with poor ESCC prognosis. These findings enhance our understanding of ESCC migration and HDACi therapy.
Core Tip: This study revealed that trichostatin A (TSA), a histone deacetylase inhibitor (HDACi), promoted the migration of esophageal squamous cell carcinoma (ESCC) cells by facilitating epithelial-mesenchymal transition (EMT) through the bromodomain-containing protein (BRD4)/cellular myelocytomatosis oncogene (c-Myc)/endoplasmic reticulum (ER) stress pathway. Mechanistically, TSA-induced histone acetylation enhances BRD4 recruitment and c-Myc expression, which triggers ER stress and subsequently drives EMT. Clinical analyses demonstrated a negative correlation between histone acetylation levels and ESCC prognosis, providing novel insights into the molecular mechanisms of ESCC migration and the implications of HDACi therapy.
