1. Cancer Biology
  2. Chromosomes and Gene Expression
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Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence

  1. Shou Liu
  2. Wenjian Cao
  3. Yichi Niu
  4. Jiayi Luo
  5. Yanhua Zhao
  6. Zhiying Hu
  7. Chenghang Zong  Is a corresponding author
  1. Baylor College of Medicine, United States
Research Article
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Cite this article as: eLife 2021;10:e64204 doi: 10.7554/eLife.64204

Abstract

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.

Data availability

Sequencing data have been deposited in GEO under GSE160444

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Shou Liu

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wenjian Cao

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yichi Niu

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4376-7792
  4. Jiayi Luo

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9873-0671
  5. Yanhua Zhao

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Zhiying Hu

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Chenghang Zong

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    For correspondence
    czong@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8337-8038

Funding

NIH Office of the Director (1DP2EB020399)

  • Chenghang Zong

Robert and Janice McNair Foundation (McNair Scholarship)

  • Chenghang Zong

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

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.

Reviewing Editor

  1. Maureen E Murphy, The Wistar Institute, United States

Publication history

  1. Received: October 20, 2020
  2. Accepted: May 12, 2021
  3. Accepted Manuscript published: May 13, 2021 (version 1)

Copyright

© 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.

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