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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-04-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-021-00248-2 |
| _version_ | 1797641701029838848 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T13:49:29Z |
| format | Article |
| id | doaj.art-b80593287fd5486295801c1046cbf0bb |
| institution | Directory Open Access Journal |
| issn | 2374-4677 |
| language | English |
| last_indexed | 2024-03-11T13:49:29Z |
| publishDate | 2021-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj.art-b80593287fd5486295801c1046cbf0bb2023-11-02T09:30:19ZengNature Portfolionpj Breast Cancer2374-46772021-04-017111510.1038/s41523-021-00248-2SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2Gaurav A. Mehta0Steven P. Angus1Christen A. Khella2Kevin Tong3Pooja Khanna4Shelley A. H. Dixon5Michael P. Verzi6Gary L. Johnson7Michael L. Gatza8Department of Radiation Oncology, Robert Wood Johnson Medical SchoolDepartment of Pediatrics, Indiana University School of MedicineDepartment of Radiation Oncology, Robert Wood Johnson Medical SchoolRutgers Cancer Institute of New JerseyDepartment of Radiation Oncology, Robert Wood Johnson Medical SchoolDepartment of Pediatrics, Indiana University School of MedicineRutgers Cancer Institute of New JerseyDepartment of Pharmacology, University of North Carolina School of MedicineDepartment of Radiation Oncology, Robert Wood Johnson Medical SchoolAbstract 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.https://doi.org/10.1038/s41523-021-00248-2 |
| spellingShingle | 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 npj Breast Cancer |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41523-021-00248-2 |
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