Chromatin rewiring by mismatch repair protein MSH2 alters cell adhesion pathways and sensitivity to BET inhibition in gastric cancer

• Main Authors: Nargund, Amrita M., Xu, Chang, Mandoli, Amit, Okabe, Atsushi, Chen, Gao Bin, Huang, Kie Kyon, Sheng, Taotao, Yao, Xiaosai, Teo, Jia Ming Nickolas, Sundar, Raghav, Kok, Yee Jiun, See, Yi Xiang, Xing, Manjie, Li, Zhimei, Yong, Chern Han, Anand, Aparna, Fazreen, A. I. Zul, Poon, Lai Fong, Ng, Michelle Shu Wen, Koh, Javier Yu Peng, Ooi, Wen Fong, Tay, Su Ting, Ong, Xuewen, Tan, Angie Lay Keng, Grabsch, Heike I., Fullwood, Melissa Jane, Teh, Tean Bin, Bi, Xuezhi, Kaneda, Atsushi, Li, Shang, Tan, Patrick
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Medicine; Mutations; Protein
• Online Access: https://hdl.handle.net/10356/163560
• Institution: Nanyang Technological University

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.