Disrupting YAP phase separation attenuates the development of primary liver cancer in animal models

In these murine liver cancer samples, we used specific antibody detection to find endogenous YAP formation condensates in the focal area, a phenomenon also observed in human liver cancer tissues. Deletion, mutagenesis and replacement assays of the coiled-coil (CC) domain demonstrate a critical role of activated YAP condensation in c-Myc-induced hepatoma, myr-AKT-induced intrahepatic cholangiocarcinoma, and N90-CTNNB1-induced hepatoblastoma. Transcriptome sequencing revealed that YAP phase separation inhibits AMPK activation and promotes c-Myc-induced hepatoma development. Our research indicates that condensates driven by YAP phase separation enrich TAK1, an AMPK-activated upstream kinase, potentially creating a physical barrier to AMPK phosphorylation activation. In addition, we further demonstrated that a specific peptide derived from TEAD1 disrupts the formation of YAP condensates and attenuates the development of these primary liver cancers. Overall design: Transcriptomic sequencing was conducted on liver cancer tissues induced by YAP-S127A/c-Myc and YAP-S127A-4LE/c-Myc.