Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells
Version 2 2021-12-21, 03:31Version 2 2021-12-21, 03:31
Version 1 2021-01-18, 19:45Version 1 2021-01-18, 19:45
journal contribution
posted on 2021-12-21, 03:31 authored by NT Pfister, V Fomin, K Regunath, JY Zhou, W Zhou, L Silwal-Pandit, WA Freed-Pastor, O Laptenko, SP Neo, J Bargonetti, Paul NeilsenPaul Neilsen© 2015, Pfister et al. Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that > 40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of theSWI/SNFchromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to antiVEGFtherapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential.
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29Issue
12Start Page
1298End Page
1315Number of Pages
19eISSN
1549-5477ISSN
0890-9369Publisher
Cold Spring Harbor Laboratory PressPublisher DOI
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Columbia University; Oslo University Hospital; Massachusetts General Hospital; Agency for Science, Technology, and Research, Singapore; City University of New York; Rutgers New Jersey Medical School; National University of Singapore; Swinburne University of TechnologyEra Eligible
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