Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming
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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. Copyright 2020, The Author(s).
SponsorsThis work was supported in part by the NIH/NCI grants P50CA228991, P30CA006973, R21CA165807, R01CA215483, R01CA129080, ACS RSG-18-028-01, by the Department of Defense (DoD) grants W81XWH-11-2-0230/OC100517, by the Ovarian Cancer Research Alliance, the Honorable Tina Brozman Foundation, the Endometriosis Foundation of America, and the Gray Foundation, and by the Richard W. TeLinde Endowment Fund from the Department of Gynecology and Obstetrics, Johns Hopkins University,
Gene Regulatory Networks
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85085868708&doi=10.1038%2fs41467-020-16416-0&partnerID=40&md5=3e9b85d81585517b8827e626f5794ada; http://hdl.handle.net/10713/13114