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Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer

  1. Author:
    Antonucci, Laura
    Li, Na
    Duran, Angeles [ORCID]
    Cobo, Isidoro
    Nicoletti, Chiara [ORCID]
    Watari, Kosuke [ORCID]
    Nandi, Shuvro Prokash [ORCID]
    Zhu,Feng
    Zhao,Yongmei [ORCID]
    Riahi, Irene
    Tsuda, Motoyuki
    Shah, Vidhi M
    Morgan, Terry
    Waugh, Trent
    Caputo, Luca [ORCID]
    Liu, Yuan
    Rundberg Nilsson, Alexandra [ORCID]
    Xian, Hongxu
    Todoric, Jelena
    Gu, Li [ORCID]
    Sanchez-Lopez, Elsa
    Eibl, Guido
    Vucic, Emily A
    Krawczyk, Michal
    Xu, Qianlan
    Lowy, Andrew M
    Hatzivassiliou, Georgia
    Roose-Girma, Merone
    Skowronska-Krawczyk, Dorota [ORCID]
    Scott, David A [ORCID]
    Bar-Sagi, Dafna
    Tamayo, Pablo
    Wu, Ying
    Sears, Rosalie C [ORCID]
    Glass, Christopher K
    Alexandrov, Ludmil B [ORCID]
    Puri, Pier Lorenzo
    Dawson, David W
    Hu, Yinling [ORCID]
    Diaz-Meco, Maria T [ORCID]
    Moscat, Jorge [ORCID]
    Karin, Michael [ORCID]

  2. Author Address

    Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego School of Medicine, La Jolla, CA, USA., Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Jinan, China., Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA., Division of Clinical Immunology & Rheumatology, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Comprehensive Arthritis, Musculoskeletal, Bone and Autoimmunity Center, University of Alabama at Birmingham, Birmingham, AL, USA., Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA., Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., CCR Sequencing Facility Bioinformatics Group, Bioinformatics and Computational Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Departments of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA., Department of Molecular and Medical Genetics, School of Medicine Oregon Health and Science University, Portland, OR, USA., Brenden-Colson Center for Pancreatic Care, School of Medicine Oregon Health and Science University, Portland, OR, USA., Department of Pathology, School of Medicine Oregon Health and Science University, Portland, OR, USA., Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria., Department of Orthopedic Surgery, University of California, San Diego School of Medicine, La Jolla, CA, USA., Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA., Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA., Department of Physiology and Biophysics, Center for Translational Vision Research, School of Medicine, University of California, Irvine, Irvine, CA, USA., Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA., Genentech, Inc., San Francisco, CA, USA., Cancer Metabolism Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Center for Novel Therapeutics and Division of Medical Genetics, Department of Medicine, Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA., Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA., Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA., Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego School of Medicine, La Jolla, CA, USA. karinoffice@health.ucsd.edu.,
    1. Year: 2025
    2. Date: Jun 30
    3. Epub Date: 2025 06 30
  2. Journal: Nature Cancer
  4. Type of Article: Article
  1. Abstract:

    Pancreatic ductal adenocarcinoma (PDAC) emerges from mutant KRAS-harboring but dormant low-grade pancreatic intraepithelial neoplasia (PanIN). To examine the role of oxidative stress, a putative PDAC risk factor, we established an organoid-based transformation system. Although the prototypic oxidant H2O2 induced organoid transformation, its effect was nonmutational and was mediated by the oxidant-responsive transcription factor NRF2, which induced the histone methyltransferase EZH2. Congruently, nonoxidizing NRF2 activators triggered organoid malignant conversion through NRF2 and EZH2, establishing a hitherto unknown epigenetic mechanism underlying PanIN-to-PDAC progression. While NRF2 induced EZH2 gene transcription in mouse and human PDAC, EZH2, a general repressor, coactivated transcription of NRF2-encoding NFE2L2 and interacted with other transcription factors to induce genes that sustain PDAC metabolic demands. The self-amplifying NRF2-EZH2 epigenetic loop also accounted for inflammation-driven PanIN-to-PDAC progression in vivo and was upregulated in established human PDAC, whose malignancy was maintained by NRF2 binding to the EZH2 promoter. © 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.

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  2. DOI: 10.1038/s43018-025-01003-3
  3. PMID: 40588523
  4. PII : 10.1038/s43018-025-01003-3

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  1. Fiscal Year: FY2024-2025
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