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.

Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4 / Zanconato, Francesca; Battilana, Giusy; Forcato, Mattia; Filippi, Letizia; Azzolin, Luca; Manfrin, Andrea; Quaranta, Erika; Di Biagio, Daniele; Sigismondo, Gianluca; Guzzardo, Vincenza; Lejeune, Pascale; Haendler, Bernard; Krijgsveld, Jeroen; Fassan, Matteo; Bicciato, Silvio; Cordenonsi, Michelangelo; Piccolo, Stefano. - In: NATURE MEDICINE. - ISSN 1078-8956. - 24:10(2018), pp. 1599-1610. [10.1038/s41591-018-0158-8]

Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4

Forcato, Mattia;Bicciato, Silvio;
2018

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.
2018
17-set-2018
24
10
1599
1610
Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4 / Zanconato, Francesca; Battilana, Giusy; Forcato, Mattia; Filippi, Letizia; Azzolin, Luca; Manfrin, Andrea; Quaranta, Erika; Di Biagio, Daniele; Sigismondo, Gianluca; Guzzardo, Vincenza; Lejeune, Pascale; Haendler, Bernard; Krijgsveld, Jeroen; Fassan, Matteo; Bicciato, Silvio; Cordenonsi, Michelangelo; Piccolo, Stefano. - In: NATURE MEDICINE. - ISSN 1078-8956. - 24:10(2018), pp. 1599-1610. [10.1038/s41591-018-0158-8]
Zanconato, Francesca; Battilana, Giusy; Forcato, Mattia; Filippi, Letizia; Azzolin, Luca; Manfrin, Andrea; Quaranta, Erika; Di Biagio, Daniele; Sigismondo, Gianluca; Guzzardo, Vincenza; Lejeune, Pascale; Haendler, Bernard; Krijgsveld, Jeroen; Fassan, Matteo; Bicciato, Silvio; Cordenonsi, Michelangelo; Piccolo, Stefano
File in questo prodotto:
File Dimensione Formato  
Piccolo Zanconato MAIN.pdf

Open Access dal 02/04/2019

Tipologia: Versione dell'autore revisionata e accettata per la pubblicazione
Dimensione 2.33 MB
Formato Adobe PDF
2.33 MB Adobe PDF Visualizza/Apri
zanconato2018.pdf

Accesso riservato

Tipologia: Versione pubblicata dall'editore
Dimensione 2.92 MB
Formato Adobe PDF
2.92 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1167080
Citazioni
  • ???jsp.display-item.citation.pmc??? 119
  • Scopus 203
  • ???jsp.display-item.citation.isi??? 201
social impact