CCT3 acts upstream of YAP and TFCP2 as a potential target and tumour biomarker in liver cancer

作者：Ya Liu, Xiao Zhang, Jiafei Lin, Yuxin Chen, Yongxia Qiao, Susu Guo, Yueyue Yang, Guo‐Qing Zhu, Qiuhui Pan, Jiayi Wang, Fenyong Sun · 发表于：Cell Death and Disease · 年份：2019 · DOI：10.1038/s41419-019-1894-5 · 被引用次数：120 · 研究领域：Hippo pathway signaling and YAP/TAZ、Heat shock proteins research、Ubiquitin and proteasome pathways

Although Yes-associated protein (YAP) is very important to liver cancer, its nuclear localisation prevents consideration as a promising therapeutic target and a diagnostic biomarker. Recently, we reported that the protumourigenic roles of YAP in liver cancer are indispensable for transcription factor CP2 (TFCP2) in a Hippo-independent manner; however, proteins that act upstream to simultaneously control YAP and TFCP2 remain unclear. The aim of this study was to uncover such proteins and evaluate whether they are potential YAP-associated therapeutic targets and diagnostic biomarkers. Mass spectrometry revealed that chaperonin containing TCP1 subunit 3 (CCT3) co-interact with YAP and TFCP2, and notably, CCT3 is a non-nuclear protein. CCT3 was elevated in liver cancer, and its higher expression was associated with poorer overall survival. Inhibiting CCT3 resulted in a suppressed transformative phenotype in liver cancer cells, suggesting that CCT3 might be a potential therapeutic target. CCT3 prolonged half-life of YAP and TFCP2 by blocking their ubiquitination caused by poly(rC) binding protein 2 (PCBP2) in a beta-transducin repeat containing E3 ubiquitin protein ligase (βTrCP)-independent manner. Interestingly, PCBP2 directly interacted with YAP via a WB motif-WW domain interaction, whereas indirectly interacted with TFCP2 via the aid of YAP. Furthermore, CCT3 was capable of separating PCBP2-YAP interactions, thereby preventing YAP and TFCP2 from PCBP2-induced ubiquitination. M...