Yu Man, Wang Jingning, Zhang Xiao, Zhang Haoran, Li Chaoqiang, Li Juebei, Lin Jiaming, Zheng Jie, Huang Liu, Li Yan, Sun Shuguo
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.
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.
Nat Commun. 2025 Apr 24;16(1):3855. doi: 10.1038/s41467-025-59309-w.
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.
转录共激活因子Yes相关蛋白（YAP）和含PDZ结合基序的转录共激活因子（TAZ）通过转录输出在癌症中发挥关键作用。然而，它们的反式激活机制仍不清楚，且缺乏有效的靶向策略。在此，我们表明YAP/TAZ具有一个疏水反式激活结构域（TAD）。TAD敲除由于生长缺陷而阻止肿瘤形成，并增强免疫攻击。从机制上讲，TAD通过招募依赖于TATA结合蛋白相关因子4（TAF4）的TFIID复合物促进起始前复合物（PIC）组装，并通过依赖于中介体复合物亚基15（MED15）的中介体招募增强RNA聚合酶II（Pol II）延伸，以促进致癌/免疫抑制程序的表达。合成肽TJ-M11选择性破坏TAD与MED15和TAF4的相互作用，抑制肿瘤生长并使肿瘤对免疫疗法敏感。我们的研究结果表明，YAP/TAZ TAD通过疏水相互作用在PIC组装和Pol II延伸中发挥双重功能，这代表了癌症治疗和联合免疫治疗的可操作靶点。
