Abstract C37: Setdb1 is required for formation of pancreatic ductal adenocarcinoma by inhibiting apoptosis through regulation of p53 expression

Epigenetics is one of the representative mutation signatures in human pancreatic ductal adenocarcinoma (PDAC). Histone modification, one group of epigenetic regulators, is known to play an important role in cancer development. Setdb1, a histone methyltransferase that trimethylates histone H3 on lysine 9, has been reported to promote 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 PDAC formation. Setdb1 was expressed in pancreatic ductal cells and a subset of pancreatic acinar cells in wild-type mice. In pancreatic specific Setdb1 conditional KO mice, no abnormality was observed in pancreatic development. However, pancreatic deletion of Setdb1 resulted in pancreatic atrophy concomitant with increased apoptosis and upregulated p53 expression after cerulein-induced pancreatitis. To investigate the impact of pancreatic Setdb1 deletion in the context of oncogenic Kras, we next generated Ptf1a-Cre; KrasG12D; Setdb1f/f (KCS) mice and compared to control Ptf1a-Cre; KrasG12D (KC) mice. Pancreatic deletion of Setdb1 significantly accelerated spontaneous development of acinar-to-ductal metaplasia (ADM) and pancreatic intraepitherial neoplasia (PanIN) in KCS mice at the age of 4 weeks. Additionally, immunostaining revealed a dramatic increase in apoptotic cells and upregulated p53 expression in KCS mice. Consistently, microarray analysis revealed upregulated expression of apoptotic signaling pathway and p53 downstream gene pathway in KCS mice compared to KC mice. Furthermore, Chromatin immunoprecipitation experiments in acinar cells isolated from wild-type mice revealed that Setdb1 bound to the promoter regions of p53 to support its expression. Given that Setdb1 loss caused increased apoptosis mediated by p53, we next examined the impact of pancreatic Setdb1 deletion on PDAC formation in the context of heterozygous p53 deletion. Surprisingly, PDAC formation was suppressed in KCS mice in the context of heterozygous p53 deletion (KPheteroCS mice). Again, apoptosis was increased and p53 expression was upregulated in KPheteroCS mice compared to KPheteroC mice. Furthermore, KPheteroCS mice showed significantly better prognosis for survival compared to control KPheteroC mice. In sharp contrast, in KCS mice in the context of homozygous p53 deletion, PDAC was formed and increased apoptosis was cancelled. Additionally, suppression of Setdb1 in