Function of YAP in cancer and identification of therapeutic targets for YAP-driven tumorigenesis

Abstract

Recent evidence suggests that hyperactive YAP is a versatile mediator of malignant processes in human cancer. Here I investigate the activation of YAP by mechanical stress in acral melanoma models. Because therapeutic targeting of the Hippo-YAP pathway has been challenging due to its low druggability and limited knowledge of YAP regulatory mechanisms in cancer, I also present a systematic functional screening and validation to identify novel therapeutic targets for YAP-driven cancers. I conducted siRNA library screening using an oncogenic YAP activation model and identified MK5 as a positive regulator of YAP activity. Depletion of MK5 causes degradation and cytoplasmic retention of YAP. MK5 physically interacts with YAP and prevents its ubiquitination and proteasomal degradation. MK5-YAP interaction counteracts CK1δ/ε–mediated YAP degradation independent of LATS1/2, the core Hippo kinases. MK5 depletion suppresses the growth of xenografted LATS1/2-null tumors as well as uveal melanoma (UVM) and malignant mesothelioma (MM) cells. Moreover, MK5 expression is associated with higher levels of YAP expression in human UVM tissues, and a MK5-related gene signature correlates with poor prognosis of UVM and MM. These results discover MK5 as a novel component of YAP protein stability regulation counteracting CK1δ/ε function. Therefore, targeting the YAP degradation pathway controlled by MK5 is a potential strategy for inhibiting YAP activity in cancer.