title: Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells.
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.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
authors.forename: Neil T
authors.initials: NT
authors.lastname: Pfister
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
authors.forename: Vitalay
authors.initials: V
authors.lastname: Fomin
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
authors.forename: Kausik
authors.initials: K
authors.lastname: Regunath
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
authors.forename: Jeffrey Y
authors.initials: JY
authors.lastname: Zhou
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radiumhospital, 0310 Oslo, Norway; The K.G. Jebsen Center for Breast Cancer Research, Faculty of Medicine, Institute for Clinical Medicine, University of Oslo, 0450 Oslo, Norway;
authors.forename: Laxmi
authors.initials: L
authors.lastname: Silwal-Pandit
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
authors.forename: William A
authors.initials: WA
authors.lastname: Freed-Pastor
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
authors.forename: Oleg
authors.initials: O
authors.lastname: Laptenko
authors.affiliation: Quantitative Proteomics Group, Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore S138673;
authors.forename: Suat Peng
authors.initials: SP
authors.lastname: Neo
authors.affiliation: Department of Biological Sciences, Hunter College, City University of New York, New York, New York 10065, USA;
authors.forename: Jill
authors.initials: J
authors.lastname: Bargonetti
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA;
authors.forename: Mainul
authors.initials: M
authors.lastname: Hoque
authors.affiliation: Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA;
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.affiliation: Quantitative Proteomics Group, Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore S138673; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597;
authors.forename: Jayantha
authors.initials: J
authors.lastname: Gunaratne
authors.affiliation: The K.G. Jebsen Center for Breast Cancer Research, Faculty of Medicine, Institute for Clinical Medicine, University of Oslo, 0450 Oslo, Norway; Department of Oncology, Oslo University Hospital, 0424 Oslo, Norway;
authors.forename: Olav
authors.initials: O
authors.lastname: Engebraaten
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
authors.forename: James L
authors.initials: JL
authors.lastname: Manley
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radiumhospital, 0310 Oslo, Norway; The K.G. Jebsen Center for Breast Cancer Research, Faculty of Medicine, Institute for Clinical Medicine, University of Oslo, 0450 Oslo, Norway;
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Swinburne University of Technology, Kuching 93350, Sarawak, Malaysia.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Neilsen
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York 10027, USA;
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
mesh_terms: D001943:Breast Neoplasms / Q000503:physiopathology*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D009154:Mutation / Q000235:genetics; D009707:Nucleosomes / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D009707:Nucleosomes; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: 3D culture; SWI/SNF; VEGFR2; breast cancer; chromatin; mutant p53; transcription