title: BPTF is required for c-MYC transcriptional activity and in vivo tumorigenesis.
abstract: c-MYC oncogene is deregulated in most human tumours. Histone marks associated with transcriptionally active genes define high-affinity c-MYC targets. The mechanisms involved in their recognition by c-MYC are unknown. Here we report that c-MYC interacts with BPTF, a core subunit of the NURF chromatin-remodelling complex. BPTF is required for the activation of the full c-MYC transcriptional programme in fibroblasts. BPTF knockdown leads to decreased c-MYC recruitment to DNA and changes in chromatin accessibility. In Bptf-null MEFs, BPTF is necessary for c-MYC-driven proliferation, G1-S progression and replication stress, but not for c-MYC-driven apoptosis. Bioinformatics analyses unveil that BPTF levels correlate positively with c-MYC-driven transcriptional signatures. In vivo, Bptf inactivation in pre-neoplastic pancreatic acinar cells significantly delays tumour development and extends survival. Our findings uncover BPTF as a crucial c-MYC co-factor required for its biological activity and suggest that the BPTF-c-MYC axis is a potential therapeutic target in cancer.
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid 28029, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Richart
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid 28029, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Carrillo-de Santa Pau
authors.affiliation: Molecular Cytogenetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Center-CNIO, Madrid 28029, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Río-Machín
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid 28029, Spain.
authors.forename: Mónica P
authors.initials: MP
authors.lastname: de Andrés
authors.affiliation: Molecular Cytogenetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Center-CNIO, Madrid 28029, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Cigudosa
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid 28029, Spain.
authors.forename: Víctor J Sánchez-Arévalo
authors.initials: VJS
authors.lastname: Lobo
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Center-CNIO, Madrid 28029, Spain.|Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain.
authors.forename: Francisco X
authors.identifier: http://orcid.org/0000-0001-9501-498X
authors.initials: FX
authors.lastname: Real
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis; D002460:Cell Line; D049109:Cell Proliferation; D042002:Chromatin Assembly and Disassembly; D016208:Databases, Factual; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D034961:Antigens, Nuclear; D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C489427:MYC protein, human; C489428:Myc protein, mouse; C406238:fetal Alzheimer antigen; D000092468:Bromodomain Containing Proteins