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

/ 2022, Latest Happenings, Research / By

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

 

Affiliations

  • 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.

 

Abstract

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

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