Acidic bile salt-induced DNA methylation promotes APE1 upregulation through miR-128-3p silencing in esophageal adenocarcinoma
4 affiliations
- 1Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- 2Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
- 3Department of Pathology, Columbia University, New York, NY 10032, USA;
- 4Division of Digestive and Liver Diseases and Center for Human Development, Department of Medicine, Columbia University, New York, NY 10032, USA;
Abstract
Esophageal adenocarcinoma (EAC) is an aggressive malignancy with rapidly rising incidence in Western populations and a poor 5-year survival rate of <20%. It commonly develops from Barrett’s esophagus, a metaplastic condition driven by chronic exposure to acidic bile salts (ABS). Apurinic/apyrimidinic endonuclease 1 (APE1) serves a central role in this process by coordinating DNA repair and redox signaling pathways that promote tumor cell survival, inflammation and progression. Despite its importance, the upstream regulatory mechanisms controlling APE1 in EAC remain incompletely understood. The present study aimed to identify a novel epigenetic mechanism linking reflux-induced stress to APE1 upregulation through microRNA (miR) regulation. Bioinformatics analysis of downregulated miRNAs in EAC and the 3’untranslated region of APE1 revealed that miR-128-3p has a predicted binding site within the APE1 3’untranslated region. Functional validation using luciferase reporter assays confirmed direct binding of miR-128-3p to APE1. Exposure to ABS resulted in marked suppression of miR-128-3p expression, concomitant with increased APE1 levels. Mechanistically, ABS induces DNA methyltransferase (DNMT1) expression, leading to hypermethylation of the CpG-rich miR-128-3p promoter and transcriptional silencing. DNMT1 knockdown or inhibition reversed miR-128-3p suppression and decreased promoter methylation, restoring its regulatory effect on APE1. Collectively, these findings defined a DNMT1/miR-128-3p/APE1 regulatory pathway that links reflux-induced epigenetic modifications to oncogenic signaling in EAC, highlighting potential therapeutic targets for this malignancy.
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BibTeX
@article{ballout2026acidic,
title = {{Acidic bile salt-induced DNA methylation promotes APE1 upregulation through miR-128-3p silencing in esophageal adenocarcinoma}},
author = {FARAH BALLOUT and HENG LU and LEI CHEN and DUNFA PENG and ZHENG CHEN and STEVEN CHEN and XIAODIAN SUN and ALEXANDER ZAIKA and LADAN FAZLOLLAHI and JIANWEN QUE and OLIVER McDONALD and WAEL EL-RIFAI},
journal = {Oncology reports},
year = {2026},
month = oct,
doi = {10.3892/or.2026.9216},
url = {https://europepmc.org/article/PMC/PMC13730532},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Acidic bile salt-induced DNA methylation promotes APE1 upregulation through miR-128-3p silencing in esophageal adenocarcinoma
AU - FARAH BALLOUT
AU - HENG LU
AU - LEI CHEN
AU - DUNFA PENG
AU - ZHENG CHEN
AU - STEVEN CHEN
AU - XIAODIAN SUN
AU - ALEXANDER ZAIKA
AU - LADAN FAZLOLLAHI
AU - JIANWEN QUE
AU - OLIVER McDONALD
AU - WAEL EL-RIFAI
PY - 2026
DA - 2026/10/30
JO - Oncology reports
DO - 10.3892/or.2026.9216
UR - https://europepmc.org/article/PMC/PMC13730532
AB - Esophageal adenocarcinoma (EAC) is an aggressive malignancy with rapidly rising incidence in Western populations and a poor 5-year survival rate of <20%. It commonly develops from Barrett’s esophagus, a metaplastic condition driven by chronic exposure to acidic bile salts (ABS). Apurinic/apyrimidinic endonuclease 1 (APE1) serves a central role in this process by coordinating DNA repair and redox signaling pathways that promote tumor cell survival, inflammation and progression. Despite its importance, the upstream regulatory mechanisms controlling APE1 in EAC remain incompletely understood. The present study aimed to identify a novel epigenetic mechanism linking reflux-induced stress to APE1 upregulation through microRNA (miR) regulation. Bioinformatics analysis of downregulated miRNAs in EAC and the 3’untranslated region of APE1 revealed that miR-128-3p has a predicted binding site within the APE1 3’untranslated region. Functional validation using luciferase reporter assays confirmed direct binding of miR-128-3p to APE1. Exposure to ABS resulted in marked suppression of miR-128-3p expression, concomitant with increased APE1 levels. Mechanistically, ABS induces DNA methyltransferase (DNMT1) expression, leading to hypermethylation of the CpG-rich miR-128-3p promoter and transcriptional silencing. DNMT1 knockdown or inhibition reversed miR-128-3p suppression and decreased promoter methylation, restoring its regulatory effect on APE1. Collectively, these findings defined a DNMT1/miR-128-3p/APE1 regulatory pathway that links reflux-induced epigenetic modifications to oncogenic signaling in EAC, highlighting potential therapeutic targets for this malignancy.
SN - 1021-335X
SN - 1791-2431
ER -