PT - JOURNAL ARTICLE AU - HIROYUKI KATO AU - KEISUKE TATEISHI AU - HIROAKI FUJIWARA AU - HIDEAKI IJICHI AU - KEISUKE YAMAMOTO AU - TAKUMA NAKATSUKA AU - MIWAKO KAKIUCHI AU - MAKOTO SANO AU - YOTARO KUDO AU - YOKU HAYAKAWA AU - HAYATO NAKAGAWA AU - YASUO TANAKA AU - MOTOYUKI OTSUKA AU - YOSHIHIRO HIRATA AU - MAKOTO TACHIBANA AU - YOICHI SHINKAI AU - KAZUHIKO KOIKE TI - Deletion of Histone Methyltransferase G9a Suppresses Mutant Kras-driven Pancreatic Carcinogenesis AID - 10.21873/cgp.20224 DP - 2020 Nov 01 TA - Cancer Genomics - Proteomics PG - 695--705 VI - 17 IP - 6 4099 - http://cgp.iiarjournals.org/content/17/6/695.short 4100 - http://cgp.iiarjournals.org/content/17/6/695.full SO - Cancer Genomics Proteomics2020 Nov 01; 17 AB - Background/Aim: The entire mechanisms by which epigenetic modifiers contribute to the development of pancreatic cancer remain unknown. Although the histone methyltransferase G9a is a promising target in human cancers, its role in pancreatic carcinogenesis has been under-studied. The aim of the study was to examine the role of G9a in pancreatic carcinogenesis by a gene-targeting mouse model. Materials and Methods: We established pancreas-specific G9aflox/flox mice and crossed them with Ptf1aCre/; KrasG12D/+ (KC) mice, which spontaneously develop pancreatic cancer. The phenotypes of the resulting KC mice with G9a deletion were examined. We analyzed transcriptomic data by microarray and genome-wide chromatin accessibility by transposase-accessible chromatin using sequencing. We established pancreatic organoids from KC mice. Results: G9a deficiency impaired the progression of pancreatic intraepithelial neoplasia (PanIN) and prolonged the survival of KC mice. The number of phosphorylated Erk-positive cells and Dclk1-positive cells, which are reported to be essential for the progression of PanIN, were decreased by G9a deletion. UNC0638, an inhibitor of G9a, suppressed the growth of organoids and increased global chromatin accessibility, especially around the regions including the protein phosphatase 2A genes. Conclusion: Thus, our study suggested the functional interaction of G9a, Dclk1 and Mapk pathway in the Kras-driven pancreatic carcinogenesis. The inhibition of G9a may suppress the initiation of oncogenic Kras-driven pancreatic carcinogenesis.