Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis

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Abstract
Expression of the tyrosine kinase receptor, c‐KIT, progressively decreases during local tumor growth and invasion of human melanomas. We have previously shown that enforced c‐KIT expression in highly metastatic cells inhibited tumor growth and metastasis in nude mice. Furthermore, the ligand for c‐KIT, SCF, induces apoptosis in human melanoma cells expressing c‐KIT under both in vitro and in vivo conditions. Here we show that loss of c‐KIT expression in highly metastatic cells correlates with loss of expression of the transcription factor AP‐2. The c‐KIT promoter contains three binding sites for AP‐2 and EMSA gels demonstrated that AP‐2 protein binds directly to the c‐KIT promoter. Transfection of wild‐type AP‐2 into c‐KIT‐negative A375SM melanoma cells activated a c‐KIT promoter‐driven luciferase reporter gene, while expression of a dominant‐negative AP‐2B in c‐KIT‐positive Mel‐501 cells inhibited its activation. Endogenous c‐KIT mRNA and expression of proteins were upregulated in AP‐2‐transfected cells, but not in control cells. In addition, re‐expression of AP‐2 in A375SM cells suppressed their tumorigenicity and metastatic potential in nude mice. These results indicate that the expression of c‐KIT is highly regulated by AP‐2 and that enforced AP‐2 expression suppresses tumorigenicity and metastatic potential of human melanoma cells, possibly through c‐KIT transactivation and SCF‐induced apoptosis. Therefore, loss of AP‐2 expression might be a crucial event in the development of malignant melanoma.