Jaune-Pons Emilie, Wang Xiaoyi, Mousavi Fatemeh, Klassen Zachary, El Kaoutari Abdessamad, Berger Kurt, Johnson Charis, Martin Mickenzie B, Aggarwal Saloni, Brar Sukhman, Khalid Muhammad, Ryan Joanna F, Shooshtari Parisa, Mathison Angela J, Dusetti Nelson, Urrutia Raul, Lomberk Gwen, Pin Christopher L
Department of Physiology and Pharmacology and.
Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
JCI Insight. 2024 Dec 31;10(3):e173746. doi: 10.1172/jci.insight.173746.
Enhancer of zeste homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which promotes trimethylation of lysine 27 on histone 3 (H3K27me3) and gene repression. EZH2 is overexpressed in many cancers, and studies in mice attributed both prooncogenic and tumor suppressive functions to EZH2 in pancreatic ductal adenocarcinoma (PDAC). EZH2 deletion enhances de novo KRAS-driven neoplasia following pancreatic injury, while increased EZH2 expression in patients with PDAC is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression. In this study, we examined EZH2 in pre- and early neoplastic stages of PDAC. Using an inducible model to delete the SET domain of EZH2 in adult acinar cells (EZH2ΔSET), we showed that loss of EZH2 activity did not prevent acinar cell regeneration in the absence of oncogenic KRAS (KRASG12D) nor did it increase PanIN formation following KRASG12D activation in adult mice. Loss of EZH2 did reduce recruitment of inflammatory cells and, when combined with a more aggressive PDAC model, promoted widespread PDAC progression and remodeling of the tumor microenvironment. This study suggests that expression of EZH2 in adult acinar cells restricts PDAC initiation and progression by affecting both the tumor microenvironment and acinar cell differentiation.
zeste 同源物增强子 2（EZH2）是多梳抑制复合物 2 的一部分，该复合物促进组蛋白 3 赖氨酸 27 位点的三甲基化（H3K27me3）并抑制基因表达。EZH2 在许多癌症中均有过表达，对小鼠的研究表明，EZH2 在胰腺导管腺癌（PDAC）中兼具促癌和抑癌功能。EZH2 缺失会增强胰腺损伤后 KRAS 驱动的肿瘤新生，而 PDAC 患者中 EZH2 表达增加与预后不良相关，这表明 EZH2 在 PDAC 进展中具有背景依赖性作用。在本研究中，我们检测了 PDAC 癌前和早期肿瘤阶段的 EZH2。通过使用诱导模型在成年腺泡细胞中删除 EZH2 的 SET 结构域（EZH2ΔSET），我们发现，在没有致癌性 KRAS（KRASG12D）的情况下，EZH2 活性丧失并不妨碍腺泡细胞再生，在成年小鼠中激活 KRASG12D 后，它也不会增加胰腺上皮内瘤变（PanIN）的形成。EZH2 的缺失确实减少了炎症细胞的募集，并且，当与更具侵袭性的 PDAC 模型结合时，会促进广泛的 PDAC 进展和肿瘤微环境的重塑。本研究表明，成年腺泡细胞中 EZH2 的表达通过影响肿瘤微环境和腺泡细胞分化来限制 PDAC 的起始和进展。
