Abstract
Transcriptional regulator YAP is activated in multiple human cancers and plays critical roles in tumor initiation, progression, metastasis, and drug resistance. However, therapeutic targeting of the Hippo-YAP pathway has been challenging due to its low druggability and limited knowledge of YAP regulation in cancer. Here we present a functional screen and identify a novel therapeutic target for YAP-driven tumorigenesis. RNAi screening using an oncogenic YAP activation model identified the serine/threonine kinase MK5 as a positive regulator of YAP. MK5 physically interacted with YAP and counteracted CK1δ/ε-mediated YAP ubiquitination and degradation independent of LATS1/2. MK5 kinase activity was essential for protecting YAP from ubiquitin-mediated degradation and cytoplasmic retention. Downregulating MK5 expression inhibited the survival of YAP-activated cancer cell lines and mouse xenograft models. MK5 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 cancer. These results uncover MK5 as a novel factor that regulates YAP stability, and targeting the YAP degradation pathway controlled by MK5 is a potential strategy for suppressing YAP activity in cancer. SIGNIFICANCE: These findings reveal MK5 is a novel kinase that regulates YAP in a LATS-independent manner and can be targeted for cancer therapy.
Highlights
Cancer genome sequencing efforts have uncovered several signaling pathways in which major components are frequently mutated in human cancers [1]
Coimmunoprecipitation analysis showed that MK5 inhibited the physical interaction between YAP and b-TRCP (Fig. 6K). These results indicate that MK5 counteracts Casein kinase 1d/e (CK1d/e)-mediated YAP ubiquitination
We propose a YAP stability regulation model in which MK5 binding to YAP in the cytoplasm counteracts CK1d/e-mediated YAP ubiquitination and degradation (Fig. 7J)
Summary
Cancer genome sequencing efforts have uncovered several signaling pathways in which major components are frequently mutated in human cancers [1]. Recent studies highlight the association of the Hippo–YAP pathway with principal cancer features [2, 3]. Overactivation of YAP can induce tumorigenesis, and YAP is associated with cancer stem cell properties, epithelial–mesenchymal transition, metastasis, and drug resistance [3]. Targeting the Hippo–YAP pathway is expected to be beneficial for suppressing tumorigenesis and tumor growth, and for overcoming metastasis and resistance to. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). J. Seo and M.H. Kim contributed to this article
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