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The mechanism of YAP/TAZ transactivation and dual targeting for cancer therapy

Man Yu1, Jingning Wang2, Xiao Zhang1

  • 1Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China.

Nature Communications
|April 24, 2025
PubMed

Insights

Targeting the hydrophobic transactivation domain (TAD) of YAP/TAZ proteins inhibits cancer growth and enhances immunotherapy. This discovery offers new therapeutic strategies for cancer treatment.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key drivers in cancer, but their precise mechanisms and therapeutic targeting remain elusive.
  • Understanding YAP/TAZ transactivation is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To elucidate the transactivation mechanisms of YAP/TAZ.
  • To identify YAP/TAZ transactivation domains (TADs) as potential therapeutic targets.
  • To evaluate the efficacy of targeting YAP/TAZ TADs in cancer treatment and immunotherapy.

Main Methods:

  • Investigated the role of YAP/TAZ transactivation domains (TADs) using knockout models.
  • Analyzed the recruitment of TFIID and Mediator complexes to YAP/TAZ.
  • Synthesized and tested the peptide TJ-M11 for its ability to disrupt YAP/TAZ-MED15 and YAP/TAZ-TAF4 interactions.
  • Assessed the impact of TJ-M11 on tumor growth and immune response.

Main Results:

  • YAP/TAZ possess a hydrophobic transactivation domain (TAD) essential for tumor establishment.
  • TAD knockout leads to growth defects and increased immune surveillance.
  • YAP/TAZ TADs facilitate preinitiation complex (PIC) assembly via TAF4-dependent TFIID recruitment.
  • TADs enhance RNA polymerase II (Pol II) elongation through MED15-dependent Mediator recruitment.
  • The peptide TJ-M11 selectively inhibits TAD interactions, suppressing tumor growth and enhancing immunotherapy.

Conclusions:

  • YAP/TAZ TADs have dual roles in PIC assembly and Pol II elongation through hydrophobic interactions.
  • YAP/TAZ TADs are actionable targets for cancer therapy.
  • Targeting YAP/TAZ TADs demonstrates potential for combination immunotherapy strategies.

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