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

作者：Man Yu, Jingning Wang, Xiao Zhang, Haoran Zhang, Chaoqiang Li, Juebei Li, Jiaming Lin, Jie Zheng, Liu Huang, Yan Li, Shuguo Sun · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-59309-w · 被引用次数：9 · 研究领域：Hippo pathway signaling and YAP/TAZ

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. The mechanism underlying YAP/TAZ transactivation remains to be explored. Here the authors report that the hydrophobic transcriptional activation domains of YAP/TAZ exert dual functions on transcriptional initiation and elongation through interactions with TAF4 and MED15, which could be targeted for anti-cancer therapy.