The mechanism of YAP/TAZ transactivation and dual targeting for cancer therapy
Man Yu, Jingning Wang, Xiao Zhang, Haoran Zhang, Chaoqiang Li, Juebei Li, Jiaming Lin, Jie Zheng, Liu Huang, Yan Li, Shuguo Sun
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. 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.