EPS8L3 mediates YAP nuclear translocation and promotes liver tumorigenesis

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EPS8L3 physically interacted with YAP, which induces the transcriptional activity of YAP through cytoplasmic sequestration and proteasomal degradation. EPS8L3 kinase activity was essential for protecting YAP from ubiquitin-mediated degradation and cytoplasmic retention. Downregulating EPS8L3 expression inhibited the survival of YAP-activated cancer cell lines and mouse xenograft models. EPS8L3 upregulation was associated with high levels of YAP expression and poor prognosis in clinical tumor samples, confirming its important role for YAP activity in human HCC. These results uncover EPS8L3 as a novel factor that regulates YAP stability and that targeting the YAP degradation pathway controlled by EPS8L3 is a potential strategy for suppressing YAP activity in cancer.