RT Journal Article
SR Electronic
T1 Deletion of Histone Methyltransferase G9a Suppresses Mutant Kras-driven Pancreatic Carcinogenesis
JF Cancer Genomics - Proteomics
JO Cancer Genomics Proteomics
FD International Institute of Anticancer Research
SP 695
OP 705
DO 10.21873/cgp.20224
VO 17
IS 6
A1 HIROYUKI KATO
A1 KEISUKE TATEISHI
A1 HIROAKI FUJIWARA
A1 HIDEAKI IJICHI
A1 KEISUKE YAMAMOTO
A1 TAKUMA NAKATSUKA
A1 MIWAKO KAKIUCHI
A1 MAKOTO SANO
A1 YOTARO KUDO
A1 YOKU HAYAKAWA
A1 HAYATO NAKAGAWA
A1 YASUO TANAKA
A1 MOTOYUKI OTSUKA
A1 YOSHIHIRO HIRATA
A1 MAKOTO TACHIBANA
A1 YOICHI SHINKAI
A1 KAZUHIKO KOIKE
YR 2020
UL http://cgp.iiarjournals.org/content/17/6/695.abstract
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.