EZH2 deletion does not affect acinar regeneration but restricts progression to pancreatic cancer in mice

• DOI: 10.1172/jci.insight.173746
• Publication Date: 2024-12-31T17:00:27Z
• Authors: Emilie Jaune-Pons; Xiaoyi Wang; Fatemeh Mousavi; Zachary Klassen; Abdessamad El Kao...; Kurt Berger; Charis Johnson; Mickenzie B. Martin; Saloni Aggarwal; Sukhman Brar; Muhammad Khalid; Joanna F. Ryan; Parisa Shooshtari; Angela J. Mathison; Nelson Dusetti; Raul Urrutia; Gwen Lomberk; Christopher L. Pin
• Keywords: PRC2; Tumor progression

Enhancer of Zeste Homologue 2 (EZH2) is part the Polycomb Repressor Complex 2, which promotes trimethylation lysine 27 on histone 3 (H3K27me3) and genes repression. EZH2 overexpressed in many cancers studies mice attributed both pro-oncogenic tumor suppressive functions to pancreatic ductal adenocarcinoma (PDAC). deletion enhances de novo KRAS-driven neoplasia following injury, while increased expression PDAC patients correlated poor prognosis, suggesting a context-dependant effect for progression. In this study, we examined pre- early neoplastic stages PDAC. Using an inducible model delete SET domain adult acinar cells (EZH2∆SET), showed loss activity did not prevent cell regeneration absence oncogenic KRAS (KRASG12D), nor increase PanIN formation KRASG12D activation mice. Loss reduce recruitment inflammatory and, when combined with more aggressive model, promoted widespread progression remodeling microenvironment. This study suggests restricts initiation by affecting tumour microenvironment differentiation.