Author
Listed:
- 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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