Faculty Collaboration Database

Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer. Nat Cancer 2025 Jul;6(7):1263-1282

Date

07/01/2025

Pubmed ID

40588523

Pubmed Central ID

PMC12331375

DOI

10.1038/s43018-025-01003-3

Scopus ID

2-s2.0-105009473074 (requires institutional sign-in at Scopus site)

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.

Author List

Antonucci L, Li N, Duran A, Cobo I, Nicoletti C, Watari K, Nandi SP, Zhu F, Zhao Y, Riahi I, Tsuda M, Shah VM, Morgan T, Waugh T, Caputo L, Liu Y, Rundberg Nilsson A, Xian H, Todoric J, Gu L, Sanchez-Lopez E, Eibl G, Vucic EA, Krawczyk M, Xu Q, Lowy AM, Hatzivassiliou G, Roose-Girma M, Skowronska-Krawczyk D, Scott DA, Bar-Sagi D, Tamayo P, Wu Y, Sears RC, Glass CK, Alexandrov LB, Puri PL, Dawson DW, Hu Y, Diaz-Meco MT, Moscat J, Karin M

Author

Hongxu Xian PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Carcinoma in Situ
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Cell Transformation, Neoplastic
Enhancer of Zeste Homolog 2 Protein
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Humans
Mice
NF-E2-Related Factor 2
Neoplasm Invasiveness
Organoids
Oxidative Stress
Pancreatic Neoplasms
Proto-Oncogene Proteins p21(ras)