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<p>Pancreatic ductal adenocarcinoma (PDAC) emerges from mutant <i>KRAS</i>-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 H<sub>2</sub>O<sub>2</sub> 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 <i>EZH2</i> gene transcription in mouse and human PDAC, EZH2, a general repressor, coactivated transcription of NRF2-encoding <i>NFE2L2</i> 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 <i>EZH2</i> promoter.</p>

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

  • 期刊论文

  • 发表日期：

    2025年6月30日

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

摘要

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.