Abstract

Cancer cells rely on dysregulated gene expression. This establishes specific transcriptional addictions that may be therapeutically exploited. Yet, the mechanisms that are ultimately responsible for these addictions are poorly understood. Here, we investigated the transcriptional dependencies of transformed cells to the transcription factors YAP and TAZ. YAP/TAZ physically engage the general coactivator bromodomain-containing protein 4 (BRD4), dictating the genome-wide association of BRD4 to chromatin. YAP/TAZ flag a large set of enhancers with super-enhancer-like functional properties. YAP/TAZ-bound enhancers mediate the recruitment of BRD4 and RNA polymerase II at YAP/TAZ-regulated promoters, boosting the expression of a host of growth-regulating genes. Treatment with small-molecule inhibitors of BRD4 blunts YAP/TAZ pro-tumorigenic activity in several cell or tissue contexts, causes the regression of pre-established, YAP/TAZ-addicted neoplastic lesions and reverts drug resistance. This work sheds light on essential mediators, mechanisms and genome-wide regulatory elements that are responsible for transcriptional addiction in cancer and lays the groundwork for a rational use of BET inhibitors according to YAP/TAZ biology.

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Data availability

The RNA-seq and ChIP–seq data generated in this study have been deposited in the GEO database under accession GSE102409. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are grateful to J. C. Marine (Leuven Center for Cancer Biology), J. Kim (KAIST) for the gift of the cell lines; D. J. Pan (University of Texas), A. R. Clarke (Cardiff University), F. Camargo (Boston Children’s Hospital) and P. Chambon (University of Strasbourg) for the gifts of mice. MMTV-cre mice were purchased from The Jackson Laboratory, where they were kindly deposited by L. Hennighausen. This work is supported by the AIRC Special Program Molecular Clinical Oncology ‘5 per mille’, by an AIRC PI-Grant to S.P. and by the Epigenetics Flagship project CNR-MIUR. This project has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (DENOVOSTEM grant agreement no. 670126).

Author information

Author notes

  1. These authors contributed equally: Francesca Zanconato, Giusy Battilana.

  2. These authors jointly supervised: Michelangelo Cordenonsi, Stefano Piccolo.

Affiliations

  1. Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy

    • Francesca Zanconato
    • , Giusy Battilana
    • , Letizia Filippi
    • , Luca Azzolin
    • , Andrea Manfrin
    • , Erika Quaranta
    • , Daniele Di Biagio
    • , Michelangelo Cordenonsi
    •  & Stefano Piccolo
  2. Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy

    • Mattia Forcato
    •  & Silvio Bicciato
  3. German Cancer Research Center (DKFZ) and Heidelberg University, Heidelberg, Germany

    • Gianluca Sigismondo
    •  & Jeroen Krijgsveld
  4. Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padua School of Medicine, Padua, Italy

    • Vincenza Guzzardo
    •  & Matteo Fassan
  5. Bayer AG, Drug Discovery, Berlin, Germany

    • Pascale Lejeune
    •  & Bernard Haendler
  6. IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy

    • Stefano Piccolo

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Contributions

F.Z., M.C. and S.P. designed the study, analyzed the data and wrote the manuscript. F.Z., G.B. and L.F. performed the experiments. M.Forcato and S.B. performed the bioinformatics analysis. L.A., E.Q., D.D.B., V.G. and M.Fassan performed the animal experiments and the histological analysis. P.L. and B.H. provided the reagents and advice for the animal experiments. G.S. and J.K. performed the mass spectrometry. A.M. performed the initial experiments of this study.

Competing interests

B.H. and P.L. are employees of Bayer AG. S.P. is a consultant for and received institutional grants from Bayer AG.

Corresponding authors

Correspondence to Michelangelo Cordenonsi or Stefano Piccolo.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–7

  2. Reporting Summary

  3. Supplementary Table 1

    YAP/TAZ nuclear interactors

  4. Supplementary Table 2

    Direct YAP/TAZ target genes inhibited by JQ1

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DOI

https://doi.org/10.1038/s41591-018-0158-8

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