Enhanced nuclear localization of YAP1‐2 contributes to EGF‐induced EMT in NSCLC

Abstract

YAP1, a key mediator of the Hippo pathway, plays an important role in tumorigenesis. Alternative splicing of human YAP1 mRNA results in two major isoforms: YAP1‐1, which contains a single WW domain, and YAP1‐2, which contains two WW domains, respectively. We here investigated the functions and the underlying regulatory mechanisms of the two YAP1 isoforms in the context of EGF‐induced epithelial‐mesenchymal transition (EMT) in non‐small cell lung cancer (NSCLC). Human NSCLC cell lines express both YAP1‐1 and YAP1‐2 isoforms—although when compared to YAP1‐1, YAP1‐2 mRNA levels are higher while its protein expression levels are lower. EGF treatment significantly promoted YAP1 expression as well as EMT process in NSCLCs, whereas EGF‐induced EMT phenotype was significantly alleviated upon YAP1 knockdown. Under normal culture condition, YAP1‐1 stable expression cells exhibited a stronger migration ability than YAP1‐2 expressing cells. However, upon EGF treatment, YAP1‐2 stable cells showed more robust migration than YAP1‐1 expressing cells. The protein stability and nuclear localization of YAP1‐2 were preferentially enhanced with EGF treatment. Moreover, EGF‐induced EMT and YAP1‐2 activity were suppressed by inhibitor of AKT. Our results suggest that YAP1‐2 is the main isoform that is functionally relevant in promoting EGF‐induced EMT and ultimately NSCLC progression.