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

Antonucci, Laura ; Li, Na ; Duran, Angeles ; Cobo, Isidoro ; Nicoletti, Chiara ; Watari, Kosuke ; Nandi, Shuvro Prokash ; Zhu, Feng ; Zhao, Yongmei and Riahi, Irene , et al. (2025) In Nature Cancer
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
epub
subject
in
Nature Cancer
publisher
Nature Publishing Group
external identifiers
  • pmid:40588523
  • scopus:105009473074
ISSN
2662-1347
DOI
10.1038/s43018-025-01003-3
language
English
LU publication?
no
additional info
© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.
id
87dc483b-d054-43be-97cb-188385778599
date added to LUP
2025-07-14 16:28:02
date last changed
2025-07-17 02:48:15
@article{87dc483b-d054-43be-97cb-188385778599,
  abstract     = {{<p>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.</p>}},
  author       = {{Antonucci, Laura and Li, Na and Duran, Angeles and Cobo, Isidoro and Nicoletti, Chiara and Watari, Kosuke and Nandi, Shuvro Prokash and Zhu, Feng and Zhao, Yongmei and Riahi, Irene and Tsuda, Motoyuki and Shah, Vidhi M and Morgan, Terry and Waugh, Trent and Caputo, Luca and Liu, Yuan and Rundberg Nilsson, Alexandra and Xian, Hongxu and Todoric, Jelena and Gu, Li and Sanchez-Lopez, Elsa and Eibl, Guido and Vucic, Emily A and Krawczyk, Michal and Xu, Qianlan and Lowy, Andrew M and Hatzivassiliou, Georgia and Roose-Girma, Merone and Skowronska-Krawczyk, Dorota and Scott, David A and Bar-Sagi, Dafna and Tamayo, Pablo and Wu, Ying and Sears, Rosalie C and Glass, Christopher K and Alexandrov, Ludmil B and Puri, Pier Lorenzo and Dawson, David W and Hu, Yinling and Diaz-Meco, Maria T and Moscat, Jorge and Karin, Michael}},
  issn         = {{2662-1347}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Cancer}},
  title        = {{Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer}},
  url          = {{http://dx.doi.org/10.1038/s43018-025-01003-3}},
  doi          = {{10.1038/s43018-025-01003-3}},
  year         = {{2025}},
}