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BRD7 is a candidate tumour suppressor gene required for p53 function

Nature Cell Biology volume 12, pages 380–389 (2010)Cite this article

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Abstract

Oncogene-induced senescence is a p53-dependent defence mechanism against uncontrolled proliferation. Consequently, many human tumours harbour p53 mutations and others show a dysfunctional p53 pathway, frequently by unknown mechanisms. Here we identify BRD7 (bromodomain-containing 7) as a protein whose inhibition allows full neoplastic transformation in the presence of wild-type p53. In human breast tumours harbouring wild-type, but not mutant, p53 the BRD7 gene locus was frequently deleted and low BRD7 expression was found in a subgroup of tumours. Functionally, BRD7 is required for efficient p53-mediated transcription of a subset of target genes. BRD7 interacts with p53 and p300 and is recruited to target gene promoters, affecting histone acetylation, p53 acetylation and promoter activity. Thus, BRD7 suppresses tumorigenicity by serving as a p53 cofactor required for the efficient induction of p53-dependent oncogene-induced senescence.

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Figure 1: A genetic screen for genes required for OIS identifies BRD7.
Figure 2: Genetic interaction of BRD7 with the p53 pathway.
Figure 3: BRD7 interacts physically with p53.
Figure 4: BRD7 is required for efficient transcriptional activation of a specific subset of p53 target genes.
Figure 5: BRD7 binds to selected p53 target gene promoters in a p53-dependent fashion and affects histone acetylation and promoter activity.
Figure 6: BRD7 controls loading of p300 on the P21 promoter and affects p53 C-terminal acetylation.
Figure 7: Inhibition of BRD7 cooperates to transform primary human fibroblasts, and BRD7 expression is lost in a subset of breast tumours containing wild-type p53.

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Acknowledgements

We thank Licio Collavin for discussion; Mauro Giacca, Marina Lusic and Lucia Pattarini for access to ICGEB facilities; Thomas Dobner for providing BRD7 expression constructs; Bruno Amati for p300 expression plasmid; Roderick Bijersbergen for assistance in the RNA-mediated interference array experiment; and Joachim Oude-Vrielink and Mariette Schrier for technical assistance. This work was supported by grants from the Dutch Cancer Society (KWF) to J.D., P.M.V and R.A., a European Young Investigator (EURYI) award to R.A. and by the Centre for Biomedical Genetics (CBG) (R.A.), the European Research Council (ERC) (R.A.), the Associazione Italiana per la Ricerca sul Cancro, Ministero dell'Università e della Ricerca (G.D.S.) and by EC FP6 (contracts 503576 and 502963).

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Author notes

  1. P. Mathijs Voorhoeve

    Present address: Present address: Duke-NUS Graduate Medical School, Division of Cancer and Stem Cell Biology, 8 College Road, Singapore 169857.,

  2. Jarno Drost and Fiamma Mantovani: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands

    Jarno Drost, Ran Elkon, P. Mathijs Voorhoeve & Reuven Agami

  2. Laboratorio Nazionale CIB, Area Science Park, Padriciano 99, Trieste, 34012, Italy

    Fiamma Mantovani, Francesca Tocco, Anna Comel & Giannino Del Sal

  3. Dipartimento di Scienze della Vita, Università di Trieste, Trieste, 34100, Italy

    Fiamma Mantovani, Francesca Tocco, Anna Comel & Giannino Del Sal

  4. Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands

    Henne Holstege & Jos Jonkers

  5. The Netherlands Cancer Institute, Central Microarray Facility, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands

    Ron Kerkhoven

  6. Center for Biomedical Genetics, The Netherlands

    Reuven Agami

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Contributions

J.D., F.M. and F.T. performed most of the experimental work. J.D., F.M., R.A. and G.D.S wrote the manuscript. P.M.V., R.A. and G.D.S supervised the project. R.E. performed bioinformatical analyses regarding ChIP-sequencing and mRNA expression experiments. A.C. conducted the in vitro pull-down assays. H.H. and J.J. performed the comparative genomic hybridization analysis. R.K. conducted the ChIP-sequencing procedure. P.M.V. contributed to analyses of mRNA expression data sets of human breast tumours.

Corresponding authors

Correspondence to P. Mathijs Voorhoeve, Reuven Agami or Giannino Del Sal.

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Drost, J., Mantovani, F., Tocco, F. et al. BRD7 is a candidate tumour suppressor gene required for p53 function. Nat Cell Biol 12, 380–389 (2010). https://doi.org/10.1038/ncb2038

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