Chromatin Rewiring by Mismatch Repair Protein MSH2 Alters Cell Adhesion Pathways and Sensitivity to BET Inhibition in Gastric Cancer

Cancer Res. 2022 Jul 18;82(14):2538-2551. doi: 10.1158/0008-5472.CAN-21-2072.


Mutations in the DNA mismatch repair gene MSH2 are causative of microsatellite instability (MSI) in multiple cancers. Here, we discovered that besides its well-established role in DNA repair, MSH2 exerts a novel epigenomic function in gastric cancer. Unbiased CRISPR-based mass spectrometry combined with genome-wide CRISPR functional screening revealed that in early-stage gastric cancer MSH2 genomic binding is not randomly distributed but rather is associated specifically with tumor-associated super-enhancers controlling the expression of cell adhesion genes. At these loci, MSH2 genomic binding was required for chromatin rewiring, de novo enhancer-promoter interactions, maintenance of histone acetylation levels, and regulation of cell adhesion pathway expression. The chromatin function of MSH2 was independent of its DNA repair catalytic activity but required MSH6, another DNA repair gene, and recruitment to gene loci by the SWI/SNF chromatin remodeler SMARCA4/BRG1. Loss of MSH2 in advanced gastric cancers was accompanied by deficient cell adhesion pathway expression, epithelial-mesenchymal transition, and enhanced tumorigenesis in vitro and in vivo. However, MSH2-deficient gastric cancers also displayed addiction to BAZ1B, a bromodomain-containing family member, and consequent synthetic lethality to bromodomain and extraterminal motif (BET) inhibition. Our results reveal a role for MSH2 in gastric cancer epigenomic regulation and identify BET inhibition as a potential therapy in MSH2-deficient gastric malignancies.

Significance: DNA repair protein MSH2 binds and regulates cell adhesion genes by enabling enhancer-promoter interactions, and loss of MSH2 causes deficient cell adhesion and bromodomain and extraterminal motif inhibitor synthetic lethality in gastric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / genetics
  • Chromatin / genetics
  • DNA Helicases / genetics
  • DNA Mismatch Repair* / genetics
  • DNA-Binding Proteins / genetics
  • Germ-Line Mutation
  • Humans
  • MutL Protein Homolog 1 / genetics
  • MutS Homolog 2 Protein / genetics
  • Nuclear Proteins / genetics
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Transcription Factors / genetics


  • BAZ1B protein, human
  • Chromatin
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Transcription Factors
  • SMARCA4 protein, human
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • DNA Helicases