Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/163560
Title: Chromatin rewiring by mismatch repair protein MSH2 alters cell adhesion pathways and sensitivity to BET inhibition in gastric cancer
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
Keywords: Science::Medicine
Issue Date: 2022
Source: Nargund, A. M., Xu, C., Mandoli, A., Okabe, A., Chen, G. B., Huang, K. K., Sheng, T., Yao, X., Teo, J. M. N., Sundar, R., Kok, Y. J., See, Y. X., Xing, M., Li, Z., Yong, C. H., Anand, A., Fazreen, A. I. Z., Poon, L. F., Ng, M. S. W., ...Tan, P. (2022). Chromatin rewiring by mismatch repair protein MSH2 alters cell adhesion pathways and sensitivity to BET inhibition in gastric cancer. Cancer Research, 82(14), 2538-2551. https://dx.doi.org/10.1158/0008-5472.CAN-21-2072
Project: NMRC/STaR/0026/2015
MOH-000967–00
OFLCG18May-0003
ETPL/15-R15 GAP-0021
MOE2017-T2–1-105
NMRC/CIRG/1481/2017
H18/01/a0/020
MOE2014-T3–1-006
Journal: Cancer Research
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. 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.
URI: https://hdl.handle.net/10356/163560
ISSN: 0008-5472
DOI: 10.1158/0008-5472.CAN-21-2072
Schools: School of Biological Sciences 
Organisations: National University of Singapore
Rights: © 2022 American Association for Cancer Research. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SBS Journal Articles

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