Abstract 951: Setdb1 deletion protects against formation of pancreatic ductal adenocarcinoma through inducing apoptosis and upregulating p53 expression
Authors: Ogawa Satoshi , Fukuda Akihisa , Tsuda Motoyuki , Masuda Tomonori , Sono Makoto , Fukunaga Yuichi , Yoshikawa Takaaki , Araki Osamu , Nagao Munemasa , Goto Norihiro , Hiramatsu Yukiko , Maruno Takahisa , Shinkai Yoichi , Seno Hiroshi 
Published: August 2019

Abstract
One group of epigenetic regulators known to be altered in cancer development is histone modification. Setdb1, a histone methyltransferase that trimethylates histone H3 on lysine 9 (H3K9), has been implicated in tumorigenesis by altering the expression of oncogenes/ tumor suppressor genes. In this study, we aimed to elucidate the functional role of Setdb1 in pancreatic acinar regeneration and formation of pancreatic ductal adenocarcinoma (PDAC).
Setdb1 was expressed in pancreatic ductal cells and a small subset of pancreatic acinar cells in adult wild type mice. Upon caerulein-induced pancreatitis, Setdb1 was expressed in acinar cells and acinar to ductal metaplasia (ADM). To determine the impact of pancreatic Setdb1 deletion on acinar regeneration, we generated Ptf1a-Cre; Setdb1f/f (CS) mice and induced caerulein-pancreatitis. Pancreatic deletion of Setdb1 resulted in pancreatic atrophy concomitant with increased apoptosis of acinar cells and increased expression of p53 in CS mice after caerulein-induced pancreatitis. In addition, pancreatic acinar regeneration was delayed with persistent inflammation inCS mice.
To investigate the impact of pancreatic Setdb1 deletion on PDAC formation, we next generated Ptf1a-Cre; KrasG12D; Setdb1f/f (KCS) mice and compared to control Ptf1a-Cre; KrasG12D (KC) mice. Pancreatic deletion of Setdb1 dramatically accelerated spontaneous development of ADM and pancreatic intraepithelial neoplasia (PanIN), the most common precursor lesion of PDAC, in KCS mice compared to KC mice at the age of 4 weeks. Acinar cell culture experiments revealed that Setdb1 null acinar cells converted to ADM, at least in part, in a cell autonomous manner. Long term observation revealed massive pancreatic atrophy in KCS mice. Immunostaining revealed a dramatic increase in apoptotic cells and upregulated expression of p53 in KCS mice compared to KC mice at the age of 20 weeks. Consistently, microarray analysis revealed upregulated expression of p53 and apoptotic pathway genes in KCS mice compared to KC mice.
We next examined the impact of pancreatic Setdb1 deletion on PDAC formation in the context of p53 deletion. Surprisingly, PDAC formation was suppressed in KCS mice in the context of heterozygous p53 deletion (KPhereroCS mice). Again, apoptosis was increased and p53 expression was upregulated in KPhereroCS mice. In contrast, in the context of homozygous p53 deletion, PDAC was formed and increased apoptosis was canceled in KPhomoCS mice. These findings suggested that Setdb1 deletion protects against PDAC formation through inducing apoptosis, which is mediated by p53.
In conclusion, Setdb1 is required for normal pancreatic acinar regeneration and protects against PDAC formation though inducing apoptosis, which is mediated by p53. Thus, Setdb1 could be a therapeutic target for PDAC which retains wild p53 expression.
Citation Format: Satoshi Ogawa, Akihisa Fukuda, Motoyuki Tsuda, Tomonori Masuda, Makoto Sono, Yuichi Fukunaga, Takaaki Yoshikawa, Osamu Araki, Munemasa Nagao, Norihiro Goto, Yukiko Hiramatsu, Takahisa Maruno, Yoichi Shinkai, Hiroshi Seno. Setdb1 deletion protects against formation of pancreatic ductal adenocarcinoma through inducing apoptosis and upregulating p53 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 951.