Hiroyuki Kato1, Keisuke Tateishi2, Hiroaki Fujiwara1,3, Hideaki Ijichi1, Keisuke Yamamoto1, Takuma Nakatsuka1, Miwako Kakiuchi1, Makoto Sano1,4, Yotaro Kudo1, Yoku Hayakawa1, Hayato Nakagawa1, Yasuo Tanaka1, Motoyuki Otsuka1, Yoshihiro Hirata5, Makoto Tachibana6, Yoichi Shinkai7, Kazuhiko Koike1. 1. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 2. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan ktate-tky@umin.ac.jp. 3. Division of Gastroenterology, The Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan. 4. Division of Medical Research Planning and Development, Nihon University School of Medicine, Tokyo, Japan. 5. Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 6. Laboratory of Epigenome Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan. 7. Cellular Memory Laboratory, RIKEN Advanced Science Institute, Saitama, Japan.
Abstract
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. Copyright
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 humancancers, 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:G9adeficiency 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. Copyright
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