Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming

Yohan Suryo Rahmanto (), Wenjing Shen, Xu Shi, Xi Chen, Yu Yu, Zheng-Cheng Yu, Tsutomu Miyamoto, Meng-Horng Lee, Vivek Singh, Ryoichi Asaka, Geoffrey Shimberg, Michele I. Vitolo, Stuart S. Martin, Denis Wirtz, Ronny Drapkin, Jianhua Xuan, Tian-Li Wang () and Ie-Ming Shih ()
Additional contact information
Yohan Suryo Rahmanto: Johns Hopkins Medical Institutions
Wenjing Shen: Johns Hopkins Medical Institutions
Xu Shi: Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University
Xi Chen: Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University
Yu Yu: Johns Hopkins Medical Institutions
Zheng-Cheng Yu: Johns Hopkins Medical Institutions
Tsutomu Miyamoto: Johns Hopkins Medical Institutions
Meng-Horng Lee: Johns Hopkins University
Vivek Singh: Johns Hopkins Medical Institutions
Ryoichi Asaka: Johns Hopkins Medical Institutions
Geoffrey Shimberg: Johns Hopkins Medical Institutions
Michele I. Vitolo: Marlene and Stewart Greenebaum National Cancer Institute Cancer Center and Department of Physiology, University of Maryland
Stuart S. Martin: Marlene and Stewart Greenebaum National Cancer Institute Cancer Center and Department of Physiology, University of Maryland
Denis Wirtz: Johns Hopkins University
Ronny Drapkin: University of Pennsylvania
Jianhua Xuan: Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University
Tian-Li Wang: Johns Hopkins Medical Institutions
Ie-Ming Shih: Johns Hopkins Medical Institutions

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Somatic inactivating mutations of ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human endometrium-related malignancies. To elucidate the mechanisms underlying how ARID1A deleterious mutation contributes to tumorigenesis, we establish genetically engineered murine models with Arid1a and/or Pten conditional deletion in the endometrium. Transcriptomic analyses on endometrial cancers and precursors derived from these mouse models show a close resemblance to human uterine endometrioid carcinomas. We identify transcriptional networks that are controlled by Arid1a and have an impact on endometrial tumor development. To verify findings from the murine models, we analyze ARID1AWT and ARID1AKO human endometrial epithelial cells. Using a system biology approach and functional studies, we demonstrate that ARID1A-deficiency lead to loss of TGF-β tumor suppressive function and that inactivation of ARID1A/TGF-β axis promotes migration and invasion of PTEN-deleted endometrial tumor cells. These findings provide molecular insights into how ARID1A inactivation accelerates endometrial tumor progression and dissemination, the major causes of cancer mortality.

Date: 2020
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DOI: 10.1038/s41467-020-16416-0

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