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

The Journal of Clinical Investigation
Motoyuki TsudaHiroshi Seno

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 hu...Continue Reading

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Citations

Nov 13, 2018·Annual Review of Physiology·Yaqing ZhangMarina Pasca di Magliano
Apr 17, 2020·Frontiers in Immunology·Nancy D EbeltEdwin R Manuel
Jun 25, 2020·International Journal of Molecular Sciences·Shuai WangYuan Wang
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Jan 7, 2021·Journal of Experimental & Clinical Cancer Research : CR·Yiqi YuTaiping Zhang
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Jun 25, 2021·World Journal of Gastroenterology : WJG·Hiroki SatoYusuke Mizukami
Aug 21, 2021·The Journal of Pathology·Takaaki YoshikawaHiroshi Seno

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Datasets Mentioned

BETA
GSE93615

Methods Mentioned

BETA
PCR
ChIP
ChIP-seq
Exome Sequencing
amplicon sequencing

Software Mentioned

DAVID Bioinformatics Resources
Excel
CNACS
GraphPad Prism
GeneSpring GX
DAVID
ImageJ

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