Id genes have been demonstrated to be upregulated in a wide variety of human malignancies and their expression has been correlated with disease prognosis; however, little is known about the mechanisms of Id gene activation in tumors. We have previously shown that the helix-loop-helix transcription factor, Id1, is highly expressed in primary human melanomas during the radial growth phase and that Id1 is a transcriptional repressor of the familial melanoma gene CDKN2A. Here we use a series of melanoma cell lines that recapitulate the phenotypic characteristics of melanomas at varying stages of malignant progression to evaluate the expression levels of Id1 in this model system and determine the mechanism of Id1 dysregulation in these tumor cells. We find elevated protein levels of Id1 to be present consistently in radial growth phase tumor cells in accordance with our primary tumor data. Id1 transcript levels were also found to be elevated in these radial growth phase melanoma cells without any appreciable evidence of gene amplification and Id1 promoter activity was found to correlate with Id expression levels. We therefore conclude that Id1 expression is primarily regulated at the transcriptional level in radial growth phase melanomas and expect that therapies that target Id1 gene expression may be useful in the treatment of Id-associated malignancies.
(c) 2007 Wiley-Liss, Inc.