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

Francesca Zanconato1, Giusy Battilana1, Mattia Forcato2

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

Nature Medicine
|September 19, 2018
PubMed

Insights

Cancer cells exhibit transcriptional addictions to YAP and TAZ proteins. Inhibiting bromodomain-containing protein 4 (BRD4) disrupts these dependencies, halting tumor growth and overcoming drug resistance.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Cancer cells exhibit dysregulated gene expression, leading to "transcriptional addictions" that can be targeted therapeutically.
  • The precise mechanisms underlying these transcriptional dependencies in cancer remain incompletely understood.

Purpose of the Study:

  • To investigate the transcriptional dependencies of cancer cells on the YAP and TAZ transcription factors.
  • To elucidate the role of bromodomain-containing protein 4 (BRD4) in mediating these YAP/TAZ-driven transcriptional addictions.

Main Methods:

  • Investigated the physical interaction between YAP/TAZ and BRD4.
  • Assessed the genome-wide association of BRD4 to chromatin at enhancers and promoters.
  • Utilized small-molecule inhibitors of BRD4 to evaluate their impact on YAP/TAZ-driven gene expression and tumor progression.

Main Results:

  • YAP and TAZ physically interact with BRD4, guiding its genome-wide chromatin localization.
  • YAP/TAZ target a subset of enhancers with super-enhancer characteristics, recruiting BRD4 and RNA polymerase II.
  • BRD4 inhibition effectively suppresses YAP/TAZ-driven oncogenic activity, induces regression of established tumors, and reverses drug resistance.

Conclusions:

  • BRD4 is a critical mediator of YAP/TAZ transcriptional addiction in cancer.
  • Targeting BRD4 offers a promising therapeutic strategy for YAP/TAZ-dependent cancers.
  • Understanding YAP/TAZ-BRD4 interactions provides a basis for rational therapeutic interventions using BET inhibitors.

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