Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells.

Neil T Pfister, Vitalay Fomin, Kausik Regunath, Jeffrey Y Zhou, Wen Zhou, Laxmi Silwal-Pandit, William A Freed-Pastor, Oleg Laptenko, Suat Peng Neo, Jill Bargonetti, Mainul Hoque, Bin Tian, Jayantha Gunaratne, Olav Engebraaten, James L Manley, Anne-Lise Børresen-Dale, Paul M Neilsen, Carol Prives

Index: Genes Dev. 29 , 1298-315, (2015)

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Abstract

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 the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential. © 2015 Pfister et al.; Published by Cold Spring Harbor Laboratory Press.