BPTF is required for c-MYC transcriptional activity and in vivo tumorigenesis

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.We thank the members of the Epithelial Carcinogenesis Group for valuable discussions;N. del Pozo for valuable contributions with animal experimentation; A. Picornell forvaluable contributions in an early phase of the project; M. Soengas for providing cells; M. Magnuson and C. V. Wright for providing mice; B. Amati, M. Beato, O. Fernandez-Capetillo, M. Serrano, G. Vicent and A. Sabo`for providing critical comments to prior versions of the manuscript. This work was supported, in part, by grants from Ministerio de Economıa y Competitividad, Madrid, Spain (SAF2007–60860, SAF2011–29530and ONCOBIO Consolider), Instituto de Salud Carlos III, Madrid, Spain (RTICCRD12/0036/0034), European Union Seventh Framework Programme (grant 256974), and an EIN/Roche-CNIO collaborative grant to F.X.R.; and grants from Instituto de Salud Carlos III (INTRASALUD PI12/00425 and RTICC RD12/0036/0037) to J.C.C.S