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

Author

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  • Man Yu

    (Huazhong University of Science and Technology)

  • Jingning Wang

    (Huazhong University of Science and Technology)

  • Xiao Zhang

    (Huazhong University of Science and Technology)

  • Haoran Zhang

    (Huazhong University of Science and Technology)

  • Chaoqiang Li

    (Chinese Academy of Sciences)

  • Juebei Li

    (Huazhong University of Science and Technology)

  • Jiaming Lin

    (Huazhong University of Science and Technology)

  • Jie Zheng

    (Chinese Academy of Sciences
    UCAS)

  • Liu Huang

    (Huazhong University of Science and Technology)

  • Yan Li

    (Huazhong University of Science and Technology
    Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation)

  • Shuguo Sun

    (Huazhong University of Science and Technology)

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.

Suggested Citation

  • Man Yu & Jingning Wang & Xiao Zhang & Haoran Zhang & Chaoqiang Li & Juebei Li & Jiaming Lin & Jie Zheng & Liu Huang & Yan Li & Shuguo Sun, 2025. "The mechanism of YAP/TAZ transactivation and dual targeting for cancer therapy," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59309-w
    DOI: 10.1038/s41467-025-59309-w
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    1. Nicole DelRosso & Josh Tycko & Peter Suzuki & Cecelia Andrews & Aradhana & Adi Mukund & Ivan Liongson & Connor Ludwig & Kaitlyn Spees & Polly Fordyce & Michael C. Bassik & Lacramioara Bintu, 2023. "Large-scale mapping and mutagenesis of human transcriptional effector domains," Nature, Nature, vol. 616(7956), pages 365-372, April.
    2. Zhengming Wu & Junhui Su & Fu-long Li & Tao Chen & Jaimie Mayner & Adam Engler & Shenghong Ma & Qingquan Li & Kun-Liang Guan, 2023. "YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Lei Chang & Luca Azzolin & Daniele Di Biagio & Francesca Zanconato & Giusy Battilana & Romy Lucon Xiccato & Mariaceleste Aragona & Stefano Giulitti & Tito Panciera & Alessandro Gandin & Gianluca Sigis, 2018. "The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ," Nature, Nature, vol. 563(7730), pages 265-269, November.
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