The BRG1/SOX9 Axis Is Critical for Acinar Cell-Derived Pancreatic Tumorigenesis

J Clin Invest. 2018 Aug 1;128(8):3475-3489. doi: 10.1172/JCI94287. Epub 2018 Jul 16.

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.

Keywords: Cancer; Epigenetics; Gastroenterology; Mouse models; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • DNA Helicases / biosynthesis*
  • DNA Helicases / genetics
  • Female
  • Gene Expression Regulation
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins / biosynthesis*
  • Nuclear Proteins / genetics
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Response Elements
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism*
  • Signal Transduction*
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Nuclear Proteins
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Sox9 protein, mouse
  • TP53 protein, human
  • Transcription Factors
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • SMARCA4 protein, human
  • Smarca4 protein, mouse
  • DNA Helicases

Supplementary concepts

  • Pancreatic Carcinoma