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

Author:

Suryo Rahmanto YohanORCID,Shen Wenjing,Shi XuORCID,Chen Xi,Yu YuORCID,Yu Zheng-Cheng,Miyamoto Tsutomu,Lee Meng-Horng,Singh VivekORCID,Asaka Ryoichi,Shimberg Geoffrey,Vitolo Michele I.,Martin Stuart S.,Wirtz DenisORCID,Drapkin RonnyORCID,Xuan Jianhua,Wang Tian-Li,Shih Ie-Ming

Abstract

AbstractSomatic 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.

Funder

U.S. Department of Health & Human Services | National Institutes of Health

American Cancer Society

United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs

Ovarian Cancer Research Alliance Endometriosis Foundation of America Gray Foundation Richard W. TeLinde Endowment Fund

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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