LOSS OF AP-2 RESULTS IN DOWN-REGULATION OF C-KIT AND ENHANCEMENT OF MELANOMA TUMORIGENICITY AND METASTASIS

Expression of the tyrosine kinase receptor, c-KIT, progressively decre ases during local tumor growth and invasion of human melanomas, We hav e 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 correlat es with loss of expression of the transcription factor AP-2, The c-KIT promoter contains three binding sites for AP-2 and EMSA gels demonstr ated that AP-2 protein binds directly to the c-KIT promoter. Transfect ion of wild-type AP-2 into c-KIT-negative A375SM melanoma cells activa ted a c-KIT promoter-driven luciferase reporter gene, while expression of a dominant-negative AP-2B in c-KIT-positive Mel-501 cells inhibite d its activation. Endogenous c-KIT mRNA and expression of proteins wer e upregulated in AP-2-transfected cells, but not in control cells, In addition, re-expression of AP-2 in A375SM cells suppressed their tumor igenicity and metastatic potential in nude mice. These results indicat e that the expression of c-KIT is highly regulated by AP-2 and that en forced AP-2 expression suppresses tumorigenicity and metastatic potent ial of human melanoma cells, possibly through c-KIT transactivation an d SCF-induced apoptosis, Therefore, loss of AP-2 expression might be a crucial event in the development of malignant melanoma.