Abstract
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 KrasG12D-mediated acinar-to-ductal metaplasia (ADM) and Pancreatic Intraepithelial Neoplasia (PanIN) formation in both the Pdx1-Cre and P48Cre/+ KrasG12D mouse models. Ex vivo acinar explants also show impaired EGFR-KRAS-MAPK pathway-mediated ADM upon EHMT2 deletion. Notably, KrasG12D 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 KrasG12D animals with EHMT2 inactivation have increased P21 protein levels and enhanced senescence. Furthermore, loss of EHMT2 reduces inflammatory cell infiltration typically induced during KrasG12D-mediated initiation. The inhibitory effect on KrasG12D-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.
Highlights
Pancreatic cancer remains a devastating disease, currently ranking 3rd for cancer-related deaths in the United States and predicted to rank 2nd by 2030 (Rahib et al, 2014)
Initial studies in P48Cre/+ KrasG12D mice indicated that EHMT2 deficiency prolonged survival by reducing Pancreatic Intraepithelial Neoplasia (PanINs) growth, which was accompanied by a decreased number of phosphorylated Erk-positive and Dclk1-positive cells, both populations that contribute to Pancreatic ductal adenocarcinoma (PDAC) initiation (Kato et al, 2020)
This provides data to advance our understanding of the repertoire of epigenomic regulators that support the function of oncogenes (e.g., KRAS) so as to give rise to the pancreatic cancer phenotype
Summary
Pancreatic cancer remains a devastating disease, currently ranking 3rd for cancer-related deaths in the United States and predicted to rank 2nd by 2030 (Rahib et al, 2014). Oncogenic KRAS, in particular KrasG12D, serves as the cornerstone of genetically engineered mouse models (GEMM) for PanIN lesions, as well as PDAC, when crossed to additional genetic models (Herreros-Villanueva et al, 2012). Activation of a KrasG12D allele in mice induces hyperplasia, acinar-to-ductal metaplasia (ADM), and PanIN formation (Hingorani et al, 2003). Given the lack of additional genetic events prior to higher-grade PanIN lesions, these transitions from hyperplasia and ADM through establishing low-grade PanIN are thought to occur at an epigenomic level (Shibata et al, 2018). Evidence supports that the heterogeneity of PDAC results from the presence of distinct epigenomic landscapes, which carries the potential to induce certain types of plasticity between PDAC subtypes (Lomberk et al, 2018). Dissecting the role of various epigenomic pathways should provide important insights into PDAC tumorigenesis
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