YAP Expression and Activity Are Suppressed by S100A7 via p65/NF{kappa}B-mediated Repression of {Delta}Np63

In several squamous cell carcinoma (SCC) cells, it has been previously observed that induction of the S100 calcium-binding protein A7 (S100A7) is repressed by YAP via the Hippo pathway. This report now demonstrates that S100A7 also represses YAP expression and activity by Np63 in cancer cells. Stable overexpression of S100A7 activates the NFB pathway and inhibits the expression of Np63. Caffeic acid phenethyl ester (CAPE), as a specific inhibitor of NFB, counteracts the inhibitory effect of S100A7 on the expression of Np63 and its target genes. Depletion of S100A7 significantly promotes Np63 expression. These data indicate that S100A7 acts as a suppressor of Np63. Mechanistic examination finds that Np63 not only directly binds to the region of YAP promoter and induces its expression, but also inhibits the Hippo pathway and enhances YAP activity. Importantly, either the positive correlation between S100A7 and YAP phosphorylation at S127 or the negative correlation between S100A7 and Np63 is also observed in skin SCC tissues. Chemosensitivity analysis reveals that S100A7 enhances cancer cells' resistance by inhibition of YAP expression and activity. These results demonstrate that S100A7 is an upstream modulator of the Hippo pathway and extend our understanding of S100A7 functions in cancer.

Implications: S100A7 is a new upstream regulator of the Hippo signaling pathway and reduces chemosensitivity of SCC cells through inhibitions of YAP expression and activity. Mol Cancer Res; 15(12); 1752–63. ©2017 AACR.

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