The Characteristic of S100A7 Induction by the Hippo-YAP Pathway in Cervical and Glossopharyngeal Squamous Cell Carcinoma

Abstract

S100A7 is expressed in many squamous cell carcinomas (SCCs). Our previous study revealed that S100A7 was dramatically induced in several SCC cells and activation of the Hippo pathway significantly promoted S100A7 in epidermoid carcinoma cells. However, whether the Hippo pathway regulates S100A7 expression in SCCs remains largely unknown. Here, we uncover that S100A7 induction by the Hippo-YAP pathway displays different characteristic in cervical and glossopharyngeal SCC. In well differentiated HCC94 cervical cells and FaDu pharyngeal cells, S100A7 is easily induced by both suspension and dense culture, which is accompanied by an increase in YAP phosphorylation and a decrease in nuclear YAP. Strikingly, these correlations of S100A7 and YAP reverse after recovery of cell attachment or relief from dense culture. Further examination finds that S100A7 induction is significantly repressed by nuclear YAP, which is validated by activation or inhibition of the Hippo pathway via loss- and/or gain-of- LATS1 and MST1 function. Subsequently, we prove that TEAD1 is required for YAP transcriptional repression of S100A7. However, S100A7 is hardly induced in poorly differentiated SiHa cervical cells and NCI-H226 pulmonary cells even in suspension or activation of the Hippo pathway. More importantly, cervical and lingual SCC tissues array analyses show that S100A7 expression displays the positive correlation with pYAP-S127 and the negative correlation with nuclear YAP in the majority of well differentiated but not in poorly differentiated tissues. Collectively, our findings demonstrate that the different induction of S100A7 toward activation of the Hippo pathway mainly depends on the degree of cell differentiation in cervical and glossopharyngeal SCC.

YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63

“…Interestingly, our previous study uncovered that S100A7 induction was also repressed by YAP through activation of the Hippo pathway in A431, HCC94, and FaDu cells under suspend and dense culture or F-actin disruption (8,9). Combined with the findings in this study, we conclude that there is a negative correlation of S100A7 and YAP, and reciprocal negative regulation between the two proteins in SCC cells, at least in A431, HCC94, and FaDu cells.…”

“…Although S100A7 expression is negatively regulated by nuclear YAP, both S100A7 and YAP perform the similar functions in promoting cells' proliferation and inhibiting squamous differentiation (8)(9)(10). In this report, we provide evidence that S100A7 also inhibits YAP expression and activity through p65/NFkBmediated repression of DNp63, and S100A7 represses druginduced apoptosis via inhibition of YAP.…”

“…First, overexpression of S100A7 in A431 cells promoted cell proliferation and inhibited differentiation, whereas the opposite results were obtained in silencing of S100A7 in HCC94 cells (11). Similarly, knockdown of YAP in all these three cells resulted in a decrease in the growth of cells (8,9). Second, either inhibition or activation of chemotherapy-induced apoptosis was observed in S100A7-overexpressed cells or S100A7-silenced cells, suggesting that S100A7 expression reduced the chemosensitivity in these cells.…”

“…In addition, increased S100A7 expression has been reported in nearly all types of SCC tissues as well as adenocarcinomas of the breast (3)(4)(5)(6)(7). Our recent works uncovered that the S100A7 acted as a dual regulator in promoting proliferation and suppressing differentiation in several SCC cells (8)(9)(10)(11). S100A7 has also been shown to be attributed to resistance of anoikis resulting in tumor growth by activating several signaling pathways (12,13).…”

“…S100A7 has also been shown to be attributed to resistance of anoikis resulting in tumor growth by activating several signaling pathways (12,13). Interestingly, S100A7 has been induced by cytokines, cell dense and suspension culture, and by activation of the Hippo pathway (8,9).…”