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自我放大的NRF2–EZH2表观遗传循环将KRAS激活的祖细胞转化为侵袭性胰腺癌

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

原文发布日期： 2025-06-30

英文摘要：

摘要翻译：

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自我放大的NRF2–EZH2表观遗传循环将KRAS激活的祖细胞转化为侵袭性胰腺癌

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

原文发布日期： 2025-06-30

英文摘要：

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.

摘要翻译：

胰腺导管腺癌（PDAC）起源于携带KRAS突变但处于休眠状态的低级别胰腺上皮内瘤变（PanIN）。为探究氧化应激（一种公认的PDAC风险因素）的作用，我们建立了基于类器官的转化研究体系。尽管原型氧化剂H2O2能诱导类器官转化，但其作用并非通过突变机制，而是由氧化应激响应转录因子NRF2介导——该因子可激活组蛋白甲基转移酶EZH2的表达。与此一致的是，非氧化性NRF2激活剂同样通过NRF2-EZH2轴触发类器官恶性转化，这揭示了一种此前未知的、驱动PanIN向PDAC进展的表观遗传机制。在小鼠和人类PDAC中，NRF2虽能诱导EZH2基因转录，但作为广谱转录抑制因子的EZH2却反常地共激活了NRF2编码基因NFE2L2的转录，并通过与其他转录因子相互作用诱导维持PDAC代谢需求的基因表达。这种自我放大的NRF2-EZH2表观遗传循环同样解释了炎症驱动的体内PanIN-PDAC进展过程，并在已形成的人类PDAC中持续上调——其恶性表型的维持依赖于NRF2与EZH2启动子的结合。