Transcriptional regulation in melanoma

Melanoma is one of the most chemo-resistant cancers and one whose incidence is increasing significantly. Transcription factors are DNA-binding proteins which control gene expression through recognition of specific DNA sequences within target promoter or enhancer regions, either directly or through protein-protein interactions. Many transcription factors have been shown to be oncogenes or tumor suppressors in melanoma. Some of them exhibit activities thought to be common to many cancers, whereas others are thought to be specific to melanoma or melanocytes. Each transcription factor modulates biological activities through a multitude of target genes and in many cases the transcription factor’s activity may be modulated by posttranslational modifications. Unlike enzymes or receptors, only a small fraction of transcription factors have been successfully targeted for therapeutic purposes by small molecules, the most striking examples being nuclear hormone receptors, which are transcription factors that are dependent on binding and activation by drug-like nuclear hormones (e.g., sex steroids, glucocorticoids, etc.). Understanding the regulatory mechanisms and target genes of biologically important transcription factors could lead to the identity of drug-able pathways for melanoma. This is particularly important if the spectrum of currently drug-able oncoproteins is insufficient to produce curative outcomes or if transcriptional mechanisms contribute importantly to resistance from other targeted therapeutic approaches. In this chapter, we select a number of transcription factors that have been implicated in melanoma biology (MITF, CREB, SOX10, PAX3, Snail superfamily, FOXD3, Ets family, Brn2, AP-1, AP-2, LEF/TCF/β-catenin, Notch, NF-kB, SMAD/SKI, STAT3, HIF1A, Tbx-2/3, C-MYC, and p53) and focus on their regulatory mechanisms and biological targets.