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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, painful disease with a 5-year survival rate of only 9%. Recent evidence indicates that distinct epigenomic landscapes underlie PDAC progression, identifying the H3K9me pathway as important to its pathobiology. Here, we delineate the role of Euchromatic Histone-lysine  N -Methyltransferase 2 (EHMT2), the enzyme that generates H3K9me, as a downstream effector of oncogenic KRAS during PDAC initiation and pancreatitis-associated promotion.  EHMT2  inactivation in pancreatic cells reduces H3K9me2 and antagonizes Kras  G 12 D  -mediated acinar-to-ductal metaplasia (ADM) and Pancreatic Intraepithelial Neoplasia (PanIN) formation in both the  Pdx1-Cre  and  P48   Cre/+    Kras   G 12 D   mouse models.  Ex vivo  acinar explants also show impaired EGFR-KRAS-MAPK pathway-mediated ADM upon  EHMT2  deletion. Notably, Kras  G 12 D   increases EHMT2 protein levels and EHMT2-EHMT1-WIZ complex formation. Transcriptome analysis reveals that  EHMT2  inactivation upregulates a cell cycle inhibitory gene expression network that converges on the  Cdkn1a/p21-Chek2  pathway. Congruently, pancreas tissue from  Kras   G 12 D   animals with  EHMT2  inactivation have increased P21 protein levels and enhanced senescence. Furthermore, loss of  EHMT2  reduces inflammatory cell infiltration typically induced during Kras  G 12 D  -mediated initiation. The inhibitory effect on Kras  G 12 D  -induced growth is maintained in the pancreatitis-accelerated model, while simultaneously modifying immunoregulatory gene networks that also contribute to carcinogenesis. This study outlines the existence of a novel KRAS-EHMT2 pathway that is critical for mediating the growth-promoting and immunoregulatory effects of this oncogene  in vivo , extending human observations to support a pathophysiological role for the H3K9me pathway in PDAC.

frontiers in cell and developmental biology

Inactivation of the Euchromatic Histone-Lysine N-Methyltransferase 2 Pathway in Pancreatic Epithelial Cells Antagonizes Cancer Initiation and Pancreatitis-Associated Promotion by Altering Growth and Immune Gene Expression Networks