Putative role of HIF transcriptional activity in melanocytes and melanoma biology.

Hypoxia-inducible factor-1α (HIF-1α) is a highly oxygen sensitive bHLH protein that is part of the heterodimeric HIF-1 transcription factor. Under hypoxic stress, HIF-1 activity is induced to control expression of multiple downstream target genes, including vascular endothelial growth factor (VEGF). The normal epidermis exists in a constant mild hypoxic microenvironment and constitutively expresses HIF-1α and HIF-2α. Expression of HIF-1α and/or HIF-2α has been suggested to correlate with the increased malignant potential of melanocytes, therefore, failures of melanoma therapies may be partially linked to high HIF activity. Notably, melanomas that have the V600E BRAF mutation exhibit increased HIF-1α expression. We have utilized a bioinformatics approach to identify putative hypoxia response elements (HREs) in a set of genes known to participate in the process of melanogenesis (includingTRPM1, SLC45A2, HRAS, C-KIT, PMEL and CRH). While some of the mechanistic links between these genes and the HIF pathway have been previously explored, others await further investigation. Although agents targeting HIF activity have been proposed as novel treatment modalities for melanoma, there are currently no clinical trials in progress to test their efficacy in melanoma.