The BRG1/SOX9 axis is critical for acinar cell–derived pancreatic tumorigenesis
Motoyuki Tsuda, Akihisa Fukuda, Nilotpal Roy, Yukiko Hiramatsu, Laura Leonhardt, Nobuyuki Kakiuchi, Kaja Hoyer, Satoshi Ogawa, Norihiro Goto, Kozo Ikuta, Yoshito Kimura, Yoshihide Matsumoto, Yutaka Takada, Takuto Yoshioka, Takahisa Maruno, Yuichi Yamaga, Grace E. Kim, Haruhiko Akiyama, Seishi Ogawa, Christopher V. Wright, Dieter Saur, Kyoichi Takaori, Shinji Uemoto, Matthias Hebrok, Tsutomu Chiba, Hiroshi Seno
Motoyuki Tsuda, Akihisa Fukuda, Nilotpal Roy, Yukiko Hiramatsu, Laura Leonhardt, Nobuyuki Kakiuchi, Kaja Hoyer, Satoshi Ogawa, Norihiro Goto, Kozo Ikuta, Yoshito Kimura, Yoshihide Matsumoto, Yutaka Takada, Takuto Yoshioka, Takahisa Maruno, Yuichi Yamaga, Grace E. Kim, Haruhiko Akiyama, Seishi Ogawa, Christopher V. Wright, Dieter Saur, Kyoichi Takaori, Shinji Uemoto, Matthias Hebrok, Tsutomu Chiba, Hiroshi Seno
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Research Article Gastroenterology Oncology

The BRG1/SOX9 axis is critical for acinar cell–derived pancreatic tumorigenesis

Abstract

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.

Authors

Motoyuki Tsuda, Akihisa Fukuda, Nilotpal Roy, Yukiko Hiramatsu, Laura Leonhardt, Nobuyuki Kakiuchi, Kaja Hoyer, Satoshi Ogawa, Norihiro Goto, Kozo Ikuta, Yoshito Kimura, Yoshihide Matsumoto, Yutaka Takada, Takuto Yoshioka, Takahisa Maruno, Yuichi Yamaga, Grace E. Kim, Haruhiko Akiyama, Seishi Ogawa, Christopher V. Wright, Dieter Saur, Kyoichi Takaori, Shinji Uemoto, Matthias Hebrok, Tsutomu Chiba, Hiroshi Seno

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Figure 7

BRG1 expression correlates with SOX9 expression in human PDAs.

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BRG1 expression correlates with SOX9 expression in human PDAs. (A) Immun...
(A) Immunohistochemistry for BRG1 in human PanINs and PDAs. Scale bars: 50 μm. (B) BRG1 immunohistochemistry score from patient samples with PanINs (n = 26) and PanIN-derived PDAs (n = 27). PDA samples containing PanINs are selected and BRG1 expression is scored using an IHC score ranging from 0 to 8 (low to high). Means are shown. (C) Quantification of SOX9 expression in BRG1lo or BRG1hi human PDA samples. The cut-off IHC score is 0 to 6 for low and 7 to 8 for high expression. Left: PanIN (n = 26); right: PDA (n = 27). **P < 0.01, Fisher’s exact test. (D) Plots of mRNA expression of BRG1 and SOX9 from a cohort of 150 patients in the TCGA data set. (E) The box-and-whisker plot demonstrates the differential expression for SOX9 between the BRG1hi (n = 112, the higher 75%) and BRG1lo groups (n = 38, the lower 25%) from a cohort of 150 patients in the TCGA data set. In the box-and-whisker plots, horizontal bars indicate the medians, boxes indicate 25th to 75th percentiles, and whiskers indicate minimum to maximum without outlier. ***P < 0.001, Student’s t test.