TY - JOUR
T1 - The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis
AU - Tsuda, Motoyuki
AU - Fukuda, Akihisa
AU - Roy, Nilotpal
AU - Hiramatsu, Yukiko
AU - Leonhardt, Laura
AU - Kakiuchi, Nobuyuki
AU - Hoyer, Kaja
AU - Ogawa, Satoshi
AU - Goto, Norihiro
AU - Ikuta, Kozo
AU - Kimura, Yoshito
AU - Matsumoto, Yoshihide
AU - Takada, Yutaka
AU - Yoshioka, Takuto
AU - Maruno, Takahisa
AU - Yamaga, Yuichi
AU - Kim, Grace E.
AU - Akiyama, Haruhiko
AU - Ogawa, Seishi
AU - Wright, Christopher V.
AU - Saur, Dieter
AU - Takaori, Kyoichi
AU - Uemoto, Shinji
AU - Hebrok, Matthias
AU - Chiba, Tsutomu
AU - Seno, Hiroshi
N1 - Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.
AB - Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.
UR - http://www.scopus.com/inward/record.url?scp=85051273276&partnerID=8YFLogxK
U2 - 10.1172/JCI94287
DO - 10.1172/JCI94287
M3 - Article
C2 - 30010625
AN - SCOPUS:85051273276
SN - 0021-9738
VL - 128
SP - 3475
EP - 3489
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -