(A) study on the role of MAP3K3 in YAP abundance regulation and anticancer drug resistance in cutaneous melanoma cells

Abstract

The transcription coregulator YAP plays important roles in cancer development and anticancer therapy resistance. Especially, several reports have shown that YAP plays an important role in the cancer progression, lymphatic metastasis, and resistance to BRAF inhibitors in cutaneous melanoma. Cellular YAP activity is determined by a combination of its nuclear localization and protein stability. To date, the regulation of YAP nuclear translocation has been extensively studied as represented by the study of the Hippo-YAP pathway, but the mechanism of YAP stability regulation is incompletely understood. In addition, strategies to block YAP activity in cancer by promoting YAP degradation have not been developed. In this study, I provide evidence that MAP3K3, an atypical MAP kinase, is a positive regulator of YAP stability that acts independently of LATS-mediated proteasomal degradation. MAP3K3 phosphorylates YAP at serine 405 and inhibits polyubiquitination of YAP by affecting its interaction with BTRC and FBXW7. Depletion of MAP3K3 promotes p62-mediated lysosomal degradation of YAP. An increase in MAP3K3 expression supports pro-survival activity of YAP in BRAF inhibitor resistant cutaneous melanoma cells. Furthermore, I show that IL-6 establishes a positive feedback loop between MAP3K3 and YAP in cutaneous melanoma cells. Therefore, my work identifies MAP3K3 as a target to overcome BRAF inhibitor resistance in cutaneous melanoma through YAP inhibition.