Aberrant CpG methylation of the <i>TFAP2A</i> gene constitutes a mechanism for loss of <i>TFAP2A</i> expression in human metastatic melanoma

Metastatic melanoma is a deadly treatment-resistant form of skin cancer whose global incidence is on the rise. During melanocyte transformation and melanoma progression the expression profile of many genes changes. Among these, a gene implicated in several steps of melanocyte development, <i>TFAP2A</i>, is frequently silenced; however, the molecular mechanism of <i>TFAP2A</i> silencing in human melanoma remains unknown. In this study, we measured <i>TFAP2A</i> mRNA expression in primary human melanocytes compared to 11 human melanoma samples by quantitative real-time RT-PCR. In addition, we assessed CpG DNA methylation of the <i>TFAP2A</i> promoter in these samples using bisulfite sequencing. Compared to primary melanocytes, which showed high <i>TFAP2A</i> mRNA expression and no promoter methylation, human melanoma samples showed decreased <i>TFAP2A</i> mRNA expression and increased promoter methylation. We further show that increased CpG methylation correlates with decreased <i>TFAP2A</i> mRNA expression. Using The Cancer Genome Atlas, we further identified <i>TFAP2A</i> as a gene displaying among the most decreased expression in stage 4 melanomas vs. non-stage 4 melanomas, and whose CpG methylation was frequently associated with lack of mRNA expression. Based on our data, we conclude that <i>TFAP2A</i> expression in human melanomas can be silenced by aberrant CpG methylation of the <i>TFAP2A</i> promoter. We have identified aberrant CpG DNA methylation as an epigenetic mark associated with TFAP2A silencing in human melanoma that could have significant implications for the therapy of human melanoma using epigenetic modifying drugs.