Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming
Date
2020Journal
Nature CommunicationsPublisher
Nature ResearchType
Article
Metadata
Show full item recordAbstract
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. Copyright 2020, The Author(s).Sponsors
This 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,Keyword
ARID1AEndometrium--Cancer
Carcinogenesis
Gene Regulatory Networks
Transcription, Genetic
Mice, Knockout
Identifier to cite or link to this item
https://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/10713/13114ae974a485f413a2113503eed53cd6c53
10.1038/s41467-020-16416-0
Scopus Count
Collections
Related articles
- Concurrent ARID1A and ARID1B inactivation in endometrial and ovarian dedifferentiated carcinomas.
- Authors: Coatham M, Li X, Karnezis AN, Hoang LN, Tessier-Cloutier B, Meng B, Soslow RA, Blake Gilks C, Huntsman DG, Stewart CJ, Postovit LM, Köbel M, Lee CH
- Issue date: 2016 Dec
- Establishment and characterization of VOA1066 cells: An undifferentiated endometrial carcinoma cell line.
- Authors: Wang Y, Tao VL, Shin CY, Salamanca C, Chen SY, Chow C, Köbel M, Ben-Neriah S, Farnell D, Steidl C, Mcalpine JN, Gilks CB, Huntsman DG
- Issue date: 2020
- Ovarian and endometrial endometrioid adenocarcinomas have distinct profiles of microsatellite instability, PTEN expression, and ARID1A expression.
- Authors: Huang HN, Lin MC, Tseng LH, Chiang YC, Lin LI, Lin YF, Huang HY, Kuo KT
- Issue date: 2015 Mar
- ARID1A and PI3-kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion.
- Authors: Wilson MR, Reske JJ, Holladay J, Wilber GE, Rhodes M, Koeman J, Adams M, Johnson B, Su RW, Joshi NR, Patterson AL, Shen H, Leach RE, Teixeira JM, Fazleabas AT, Chandler RL
- Issue date: 2019 Aug 7
- Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis.
- Authors: Reske JJ, Wilson MR, Holladay J, Siwicki RA, Skalski H, Harkins S, Adams M, Risinger JI, Hostetter G, Lin K, Chandler RL
- Issue date: 2021 Dec