Phase separation of YAP mediated by CC domain promotes hepatoblastoma proliferation via activation of transcription.

Abstract

Yes-associated protein (YAP), a key transcriptional co-activator associated with cell fate and tumor progression, has been reported to be a powerful driver of hepatoblastoma (HB). In this study, we investigated the mechanism underlying oncogenic role of YAP in HB. The expression of YAP in HB tissues was measured through WB and qRT-PCR. The IHC and IF were performed to determine the distribution of YAP. The phase separation of YAP was proved by living cell imaging and FRAP experiment. The effect of YAP phase separation in HB cells in vitro an in vivo were tested using CCK8, flow cytometry and xenograft tumors. YAP was overexpressed and activated in HB. Nuclear YAP formed an active transcriptional site via LLPS to recruit the crucial transcription factor TEAD4. Thus, YAP phase separation facilitated transcription of oncogenic genes and subsequently mediated chemoresistance of HB. Mechanistically, the phase separation ability of YAP depends on the coiled-coil domain, which is a typical phase-separation domain. The electrostatic interactions and hydrophobic interactions within YAP are also vital to YAP phase separation. More importantly, YAP inhibitor Verteporfin is potential treatment for HB and combination with cisplatin enhanced therapeutic efficacy. Highly expressed and active YAP exerts an oncogenic effect in HB via phase separation and provides new insights for the treatment of HB.