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

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dc.contributor.authorRahmanto, Yohan Suryoen
dc.contributor.authorShen, Wenjingen
dc.contributor.authorShi, Xuen
dc.contributor.authorChen, Xien
dc.contributor.authorYu, Yuen
dc.contributor.authorYu, Zheng-Chengen
dc.contributor.authorMiyamoto, Tsutomuen
dc.contributor.authorLee, Meng-Horngen
dc.contributor.authorSingh, Viveken
dc.contributor.authorAsaka, Ryoichien
dc.contributor.authorShimberg, Geoffreyen
dc.contributor.authorVitolo, Michele, I.en
dc.contributor.authorMartin, Stuart S.en
dc.contributor.authorWirtz, Denisen
dc.contributor.authorDrapkin, Ronnyen
dc.contributor.authorXuan, Jianhuaen
dc.contributor.authorWang, Tian-Lien
dc.contributor.authorShih, Ie-Mingen
dc.contributor.departmentElectrical and Computer Engineeringen
dc.date.accessioned2020-08-10T17:59:23Zen
dc.date.available2020-08-10T17:59:23Zen
dc.date.issued2020-06-01en
dc.description.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 ARID1A(WT) and ARID1A(KO) human endometrial epithelial cells. Using a system biology approach and functional studies, we demonstrate that ARID1A-deficiency lead to loss of TGF-beta tumor suppressive function and that inactivation of ARID1A/TGF-beta 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.en
dc.description.notesThis work was supported in part by the NIH/NCI grants P50CA228991, P30CA006973, R21CA165807, R01CA215483, R01CA129080 (I.-M.S.), ACS RSG-18-028-01 (M.I.V.), by the Department of Defense (DoD) grants W81XWH-11-2-0230/OC100517 (I.-M.S. and T.-L.W.), by the Ovarian Cancer Research Alliance, the Honorable Tina Brozman Foundation, the Endometriosis Foundation of America, and the Gray Foundation (I.-M.S. and T.-L.W.), and by the Richard W. TeLinde Endowment Fund from the Department of Gynecology and Obstetrics, Johns Hopkins University (I.-M.S.), The authors thank Asli Bahadirli-Talbott for assistance with immunohistochemistry staining.en
dc.description.sponsorshipNIH/NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P50CA228991, P30CA006973, R21CA165807, R01CA215483, R01CA129080]; Department of Defense (DoD)United States Department of Defense [W81XWH-11-2-0230/OC100517]; Ovarian Cancer Research Alliance; Honorable Tina Brozman Foundation; Endometriosis Foundation of America; Gray Foundation; Richard W. TeLinde Endowment Fund from the Department of Gynecology and Obstetrics, Johns Hopkins University; ACSAmerican Cancer Society [RSG-18-028-01]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41467-020-16416-0en
dc.identifier.issn2041-1723en
dc.identifier.issue1en
dc.identifier.other2717en
dc.identifier.pmid32483112en
dc.identifier.urihttp://hdl.handle.net/10919/99634en
dc.identifier.volume11en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleInactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogrammingen
dc.title.serialNature Communicationsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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