Chromatin Rewiring by Mismatch Repair Protein MSH2 Alters Cell Adhesion Pathways and Sensitivity to BET Inhibition in Gastric Cancer (Cancer Res, May 22)

Amrita M Nargund 1Chang Xu 2Amit Mandoli 3Atsushi Okabe 4Gao Bin Chen 5Kie Kyon Huang 6Taotao Sheng 7Xiaosai Yao 8Jia Ming Nickolas Teo 9Raghav Sundar 10Yee Jiun Kok 11Yi Xiang See 12Manjie Xing 13Zhimei Li 14Chern Han Yong 15Aparna Anand 16Zul Fazreen A I 17Lai Fong Poon 1Michelle Shu Wen Ng 8Javier Yu Peng Koh 7Wen Fong Ooi 13Su Ting Tay 18Xuewen Ong 15Angie Lay Keng Tan 18Heike I Grabsch 19Melissa Jane Fullwood 12Tean Bin Teh 7Xuezhi Bi 20Atsushi Kaneda 21Shang Li 15Patrick Tan 1



  • 1Duke-NUS Medical School, Singapore, Singapore.
  • 2Duke-NUS Medical School, — Select a state —, Singapore.
  • 3Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Radboud University, Nijmegen, Germany.
  • 4Chiba University, Chiba-shi, Chiba, Japan.
  • 5Duke-NUS Medical School, Singapore, Singapore, Singapore.
  • 6Duke-NUS Medical School, Singapore, — Select a state —, Singapore.
  • 7Duke-NUS Medical School, Singapore.
  • 8Institute of Molecular and Cell Biology, Singapore, Singapore.
  • 9University of Hong Kong, Hong Kong Island, Hong Kong Island, Hong Kong.
  • 10National University Health System, Singapore, Singapore.
  • 11Bioprocessing Technology Institute, Singapore.
  • 12Nanyang Technological University, Singapore, Singapore.
  • 13Genome Institute of Singapore, Singapore.
  • 14National Cancer Centre, Singapore, Singapore.
  • 15Duke NUS Graduate Medical School, Singapore, Singapore.
  • 16Cancer Science Institute of Singapore, Singapore.
  • 17Genome Institute of Singapore, Singapore, Singapore.
  • 18Duke NUS Medical School, Singapore, Singapore.
  • 19GROW School of Oncology and Reproduction, Maastricht University Medical Center, Maastricht, Netherlands.
  • 20Bioprocessing Technology Institute, Singapore, Singapore.
  • 21Chiba University, Chuo-ku, Chiba, Japan.



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 (GC). Unbiased CRISPR-based mass spectrometry combined with genome-wide CRISPR functional screening revealed that in early-stage GC 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 GCs was accompanied by deficient cell adhesion pathway expression, epithelial-mesenchymal transition, and enhanced tumorigenesis in vitro and in vivo. However, MSH2-deficient GCs also displayed addiction to BAZ1B, a bromodomain-containing family member, and consequent synthetic lethality to bromodomain and extra-terminal motif (BET) inhibition. Our results reveal a role for MSH2 in GC epigenomic regulation and identify BET inhibition as a potential therapy in MSH2-deficient gastric malignancies.

PMID: 35583999  DOI: 10.1158/0008-5472.CAN-21-2072