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

Laia Richart,Juan C Cigudosa,Víctor J Sánchez-Arévalo Lobo,Ana Río-Machín,Enrique Carrillo-De Santa Pau,Francisco X Real,Mónica P De Andrés

doi:10.1038/ncomms10153

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.

Highlights

The MYC oncogenes encode a family of related sequencespecific bHLHZip transcription factors (c, L- and N-MYC) that control a plethora of cellular functions including cell growth, proliferation, differentiation and apoptosis. c-MYC is deregulated in more than half of human cancers[1], often in association with aggressive, poorly differentiated tumours[2]
To assess whether BPTF is required for the transcriptional activity of c-MYC, human foreskin fibroblasts (HFFs) were stably transduced with the chimeric MYC-ER complementary DNA and infected with lentiviruses coding for either control or BPTF-targeting short-hairpin RNAs
We examined the expression of a set of well-established c-MYC targets in control and BPTF-silenced HFF MYC-ER cells by real-time quantitative reverse transcriptase PCR (RT–qPCR)

Summary

Introduction

The MYC oncogenes encode a family of related sequencespecific bHLHZip transcription factors (c-, L- and N-MYC) that control a plethora of cellular functions including cell growth, proliferation, differentiation and apoptosis. c-MYC is deregulated in more than half of human cancers[1], often in association with aggressive, poorly differentiated tumours[2]. The oncogenic potential of c-MYC stems from its function as a transcriptional regulator that binds DNA on heterodimerization with MAX3. We show that BPTF and c-MYC are present in a protein complex This interaction is critical for c-MYC function, since BPTF knockdown leads to a decrease in c-MYC binding to DNA, changes in chromatin accessibility and impaired activation of the c-MYC transcriptional programme. Consistent with this, BPTF expression in human tumours positively correlates with activation of c-MYC gene signatures. BPTF is necessary for the survival of c-MYC-overexpressing cells and for c-MYC-driven tumorigenesis in the mouse pancreas These results highlight the potential of exploiting the BPTF-MYC axis in cancer therapy

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Results

Conclusion