Melanoma cell adhesion molecule stimulates yes-associated protein transcription by enhancing CREB activity via c-Jun/c-Fos in hepatocellular carcinoma cells

Dysfunction of the yes-associated protein (YAP) signaling pathway has previously been associated with liver tumorigenesis. Recently, the membrane protein melanoma cell adhesion molecule (MCAM) was identified as a novel, hepatocellular carcinoma (HCC)-specific YAP target protein that promotes carcinogenesis in HCC. However, whether MCAM conversely regulates YAP remains unknown. The aim of the current study was to demonstrate whether and how MCAM regulates YAP in HCC cells. The present study demonstrated that MCAM has a positive effect on the regulation of YAP activity and expression. Mechanistically, MCAM stimulated YAP transcription through its downstream effector c-Jun/c-Fos heterodimer. Gain and loss of function analysis by the present study indicated that c-Jun/c-Fos is capable of inducing cAMP response element-binding protein activation, which is a transcription factor that directly binds to the YAP promoter. Finally, it was identified that an impaired transformative phenotype in MCAM- or c-Jun/c-Fos-depleted HCC cells could be partially rescued by simultaneous overexpression of YAP, suggesting that YAP may function as a downstream effector of the MCAM-c-Jun/c-Fos signaling pathway. Collectively, a complete, positive, auto-regulatory loop was established by the present study, in which YAP is not only an upstream regulator, but also a downstream target of MCAM in HCC cells.