SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2

Abstract Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulato...

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Autores principales:	Gaurav A. Mehta, Steven P. Angus, Christen A. Khella, Kevin Tong, Pooja Khanna, Shelley A. H. Dixon, Michael P. Verzi, Gary L. Johnson, Michael L. Gatza
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/b80593287fd5486295801c1046cbf0bb
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spelling	oai:doaj.org-article:b80593287fd5486295801c1046cbf0bb2021-12-02T18:15:29ZSOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR210.1038/s41523-021-00248-22374-4677https://doaj.org/article/b80593287fd5486295801c1046cbf0bb2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00248-2https://doaj.org/toc/2374-4677Abstract Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression.Gaurav A. MehtaSteven P. AngusChristen A. KhellaKevin TongPooja KhannaShelley A. H. DixonMichael P. VerziGary L. JohnsonMichael L. GatzaNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Gaurav A. Mehta Steven P. Angus Christen A. Khella Kevin Tong Pooja Khanna Shelley A. H. Dixon Michael P. Verzi Gary L. Johnson Michael L. Gatza SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2
description	Abstract Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression.
format	article
author	Gaurav A. Mehta Steven P. Angus Christen A. Khella Kevin Tong Pooja Khanna Shelley A. H. Dixon Michael P. Verzi Gary L. Johnson Michael L. Gatza
author_facet	Gaurav A. Mehta Steven P. Angus Christen A. Khella Kevin Tong Pooja Khanna Shelley A. H. Dixon Michael P. Verzi Gary L. Johnson Michael L. Gatza
author_sort	Gaurav A. Mehta
title	SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2
title_short	SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2
title_full	SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2
title_fullStr	SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2
title_full_unstemmed	SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2
title_sort	sox4 and smarca4 cooperatively regulate pi3k signaling through transcriptional activation of tgfbr2
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b80593287fd5486295801c1046cbf0bb
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SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2

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