ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that ARID1A deficiency induces global changes in the epigenetic landscape of enhancers and promoters. These broad and complex effects make it challenging to identify the driving mechanisms of ARID1A deficiency in promoting cancer progression. Here, we identified the anti-senescence effect of Arid1a deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in a mouse model. In a human cell line model, we found that ARID1A deficiency upregulates the expression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1), which plays an essential role in attenuating the senescence induced by oncogenic KRAS through scavenging reactive oxygen species (ROS). As a subunit of the SWI/SNF chromatin remodeling complex, our ATAC sequencing data showed that ARID1A deficiency increases the accessibility of the enhancer region of ALDH1A1. This study provides the first evidence that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence through the upregulation of ALDH1A1 expression.
Sequencing data have been deposited in GEO under GSE160444
ARID1A deficiency promotes pancreatic tumorigenesis by reducing KRAS-induced senescenceNCBI Gene Expression Omnibus, GSE160444.
Genomic analyses identify molecular subtypes of pancreatic cancerEuropean Genome-phenome Archive (EGA), EGAS00001000154.
Integrated Genomic Characterization of Pancreatic Ductal AdenocarcinomaGDC Data Portal: TCGA-PAAD.
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivityCancer Cell Line Encyclopedia.
Cistrome Data Browser: expanded datasets and new tools for gene regulatory analysisCistrome Data Browser, human_factor.
- Chenghang Zong
- Chenghang Zong
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#AN-6434) of Baylor College Medicine. Every effort was made to minimize suffering.
- Maureen E Murphy, The Wistar Institute, United States
- Received: October 20, 2020
- Accepted: May 12, 2021
- Accepted Manuscript published: May 13, 2021 (version 1)
© 2021, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.