SETDB1 Inhibits p53-Mediated Apoptosis and Is Required for Formation of Pancreatic Ductal Adenocarcinomas in Mice

Gastroenterology. 2020 Aug;159(2):682-696.e13. doi: 10.1053/j.gastro.2020.04.047. Epub 2020 Apr 28.

Abstract

Background & aims: SETDB1, a histone methyltransferase that trimethylates histone H3 on lysine 9, promotes development of several tumor types. We investigated whether SETDB1 contributes to development of pancreatic ductal adenocarcinoma (PDAC).

Methods: We performed studies with Ptf1aCre; KrasG12D; Setdb1f/f, Ptf1aCre; KrasG12D; Trp53f/+; Setdb1f/f, and Ptf1aCre; KrasG12D; Trp53f/f; Setdb1f/f mice to investigate the effects of disruption of Setdb1 in mice with activated KRAS-induced pancreatic tumorigenesis, with heterozygous or homozygous disruption of Trp53. We performed microarray analyses of whole-pancreas tissues from Ptf1aCre; KrasG12D; Setdb1f/f, and Ptf1aCre; KrasG12D mice and compared their gene expression patterns. Chromatin immunoprecipitation assays were performed using acinar cells isolated from pancreata with and without disruption of Setdb1. We used human PDAC cells for SETDB1 knockdown and inhibitor experiments.

Results: Loss of SETDB1 from pancreas accelerated formation of premalignant lesions in mice with pancreata that express activated KRAS. Microarray analysis revealed up-regulated expression of genes in the apoptotic pathway and genes regulated by p53 in SETDB1-deficient pancreata. Deletion of Setdb1 from pancreas prevented formation of PDACs, concomitant with increased apoptosis and up-regulated expression of Trp53 in mice heterozygous for disruption of Trp53. In contrast, pancreata of mice with homozygous disruption of Trp53 had no increased apoptosis, and PDACs developed. Chromatin immunoprecipitation revealed that SETDB1 bound to the Trp53 promoter to regulate its expression. Expression of an inactivated form of SETDB1 in human PDAC cells with wild-type TP53 resulted in TP53-induced apoptosis.

Conclusions: We found that the histone methyltransferase SETDB1 is required for development of PDACs, induced by activated KRAS, in mice. SETDB1 inhibits apoptosis by regulating expression of p53. SETDB1 might be a therapeutic target for PDACs that retain p53 function.

Keywords: Cell Death; Epigenetic Factor; Oncogene; Pancreatic Cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Binding Sites
  • Carcinoma, Pancreatic Ductal / enzymology*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Mice, Knockout
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Signal Transduction
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Transcription Factors
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • transcription factor PTF1
  • Histone-Lysine N-Methyltransferase
  • SETDB1 protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)