2. Academic Validation
  3. The mechanism of YAP/TAZ transactivation and dual targeting for cancer therapy

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

  • Nat Commun. 2025 Apr 24;16(1):3855. doi: 10.1038/s41467-025-59309-w.
Man Yu # 1,  Jingning Wang # 2,  Xiao Zhang 1,  Haoran Zhang 2,  Chaoqiang Li 3,  Juebei Li 1,  Jiaming Lin 1,  Jie Zheng 3 4,  Liu Huang 5,  Yan Li 6 7,  Shuguo Sun 8
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Department of Pathogen Biology, 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.
  • 3 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China.
  • 5 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6 Department of Pathogen Biology, 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. yanli@hust.edu.cn.
  • 7 Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China. yanli@hust.edu.cn.
  • 8 Department 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. shuguo@hust.edu.cn.
  • # Contributed equally.
PMID: 40274828 DOI: 10.1038/s41467-025-59309-w
Abstract

Transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) play key roles in cancers through transcriptional outputs. However, their transactivation mechanisms remain unclear, and effective targeting strategies are lacking. Here, we show that YAP/TAZ possess a hydrophobic transactivation domain (TAD). TAD knockout prevents tumor establishment due to growth defects and enhances immune attack. Mechanistically, TADs facilitate preinitiation complex (PIC) assembly by recruiting the TATA-binding protein-associated factor 4 (TAF4)-dependent TFIID complex and enhance RNA polymerase II (Pol II) elongation through mediator complex subunit 15 (MED15)-dependent mediator recruitment for the expressions of oncogenic/immune-suppressive programs. The synthesized peptide TJ-M11 selectively disrupts TAD interactions with MED15 and TAF4, suppressing tumor growth and sensitizing tumors to immunotherapy. Our findings demonstrate that YAP/TAZ TADs exhibit dual functions in PIC assembly and Pol II elongation via hydrophobic interactions, which represent actionable targets for Cancer therapy and combination immunotherapy.

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