CTLA-4 is a direct target of Wnt/beta-catenin signaling and is expressed in human melanoma tumors.
Our goal was to identify genes regulated by Wnt/beta-catenin signaling in melanoma cells, as this pathway has been implicated in melanocyte development and in melanoma biology. We therefore undertook transcriptional profiling of UACC 1273 human melanoma cells following treatment with recombinant Wnt-3a and found that cytotoxic T-lymphocyte antigen-4 (CTLA-4) was the most highly induced gene. We observed CTLA-4 expression in human epidermal melanocytes and in patient-derived primary melanoma tumors and found that Wnt/beta-catenin signaling elevates CTLA-4 expression in two cultured melanoma cell lines. CTLA-4 is likely a direct target of Wnt/beta-catenin signaling, as the beta-catenin responsiveness of a 1.7 kb region of the CTLA-4 promoter requires a T-cell factor-1/lymphoid enhancing factor-1 consensus site present at -114 to -119 bp from the transcriptional start site. These findings are the initial demonstration that CTLA-4 is a direct target of Wnt/beta-catenin signaling and the first report of its expression in primary melanoma tumors and melanocytes. Given the described role of CTLA-4 in inhibiting the immune response, these findings may shed light on the role of Wnt/beta catenin signaling in melanoma and on the mechanism of action of human anti-CTLA-4 antibody, currently in phase III clinical trials for the treatment of melanoma.
Shah
Kavita V
KV
Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
Chien
Andy J
AJ
Yee
Cassian
C
Moon
Randall T
RT
D015703:Antigens, CD / Q000096:biosynthesis*; D001665:Binding Sites; D060908:CTLA-4 Antigen; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism*; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D017077:Culture Media, Conditioned; D051153:Wnt Proteins; D051176:beta Catenin