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

Research output: Contribution to journalArticle

59 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1298-1315
Number of pages18
JournalGenes and Development
Volume29
Issue number12
DOIs
StatePublished - Jun 15 2015

Fingerprint

Vascular Endothelial Growth Factor Receptor-2
Chromatin Assembly and Disassembly
Breast Neoplasms
RNA Sequence Analysis
Gene Expression
Neoplasms
Vascular Endothelial Growth Factor Receptor
p53 Genes
Genes
Carcinogenesis
Up-Regulation
Endothelial Cells
Cell Line
Growth

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Keywords

  • 3D culture
  • Breast cancer
  • Chromatin
  • Mutant p53
  • SNF
  • SWI
  • Transcription
  • VEGFR2

Cite this

Pfister, N. T., Fomin, V., Regunath, K., Zhou, J. Y., Zhou, W., Silwal-Pandit, L., ... Prives, C. (2015). Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells. Genes and Development, 29(12), 1298-1315. https://doi.org/10.1101/gad.263202.115
Pfister, Neil T. ; Fomin, Vitalay ; Regunath, Kausik ; Zhou, Jeffrey Y. ; Zhou, Wen ; Silwal-Pandit, Laxmi ; Freed-Pastor, William A. ; Laptenko, Oleg ; Neo, Suat Peng ; Bargonetti, Jill ; Hoque, Mainul ; Tian, Bin ; Gunaratne, Jayantha ; Engebraaten, Olav ; Manley, James L. ; Børresen-Dale, Anne Lise ; Neilsen, Paul M. ; Prives, Carol. / Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells. In: Genes and Development. 2015 ; Vol. 29, No. 12. pp. 1298-1315.
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Pfister, NT, Fomin, V, Regunath, K, Zhou, JY, Zhou, W, Silwal-Pandit, L, Freed-Pastor, WA, Laptenko, O, Neo, SP, Bargonetti, J, Hoque, M, Tian, B, Gunaratne, J, Engebraaten, O, Manley, JL, Børresen-Dale, AL, Neilsen, PM & Prives, C 2015, 'Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells', Genes and Development, vol. 29, no. 12, pp. 1298-1315. https://doi.org/10.1101/gad.263202.115

Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells. / Pfister, Neil T.; Fomin, Vitalay; Regunath, Kausik; Zhou, Jeffrey Y.; Zhou, Wen; Silwal-Pandit, Laxmi; Freed-Pastor, William A.; Laptenko, Oleg; Neo, Suat Peng; Bargonetti, Jill; Hoque, Mainul; Tian, Bin; Gunaratne, Jayantha; Engebraaten, Olav; Manley, James L.; Børresen-Dale, Anne Lise; Neilsen, Paul M.; Prives, Carol.

In: Genes and Development, Vol. 29, No. 12, 15.06.2015, p. 1298-1315.

Research output: Contribution to journalArticle

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AU - Pfister, Neil T.

AU - Fomin, Vitalay

AU - Regunath, Kausik

AU - Zhou, Jeffrey Y.

AU - Zhou, Wen

AU - Silwal-Pandit, Laxmi

AU - Freed-Pastor, William A.

AU - Laptenko, Oleg

AU - Neo, Suat Peng

AU - Bargonetti, Jill

AU - Hoque, Mainul

AU - Tian, Bin

AU - Gunaratne, Jayantha

AU - Engebraaten, Olav

AU - Manley, James L.

AU - Børresen-Dale, Anne Lise

AU - Neilsen, Paul M.

AU - Prives, Carol

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N2 - 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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