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

Nature medicine (2018-09-19)
Francesca Zanconato, Giusy Battilana, Mattia Forcato, Letizia Filippi, Luca Azzolin, Andrea Manfrin, Erika Quaranta, Daniele Di Biagio, Gianluca Sigismondo, Vincenza Guzzardo, Pascale Lejeune, Bernard Haendler, Jeroen Krijgsveld, Matteo Fassan, Silvio Bicciato, Michelangelo Cordenonsi, Stefano Piccolo
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-BRD4 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
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Anti-Growth Associated Protein 43 Antibody, clone 9-1E12, clone 9-1E12, Chemicon®, from mouse
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Anti-WWTR1 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
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IgG from rabbit serum, reagent grade, ≥95% (SDS-PAGE), essentially salt-free, lyophilized powder
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Monoclonal ANTI-FLAG® M2-Peroxidase (HRP) antibody produced in mouse, clone M2, purified immunoglobulin, buffered aqueous glycerol solution
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Anti-Sox9 Antibody, Chemicon®, from rabbit