Gene expression profiling of enforced HOXA1 expression in melanoma cell line (SkMel30)

We recently reported an oncogenomics-guided screening approach designed to identify genetic drivers of early stage melanoma metastasis, and in this study we functionally validate the top-scoring candidate, homeobox transcription factor A1 (HOXA1), by demonstrating HOXA1s robust effects on melanoma cell invasion, metastasis and tumorigenicity. Transcriptome and pathway profiling analyses of cells expressing HOXA1 reveal up-regulation of factors involved in diverse cytokine pathways that include the TGF signaling axis, which we further demonstrate to be required for HOXA1-mediated cell invasion. Transcriptome profiling also informed HOXA1s ability to potently down-regulate expression of microphthalmia-associated transcription factor (MITF) and other genes required for melanocyte differentiation, suggesting a mechanism by which HOXA1 expression de-differentiates cells into a pro-invasive precursor cell state concomitant with TGF activation. Our analysis of publicly available datasets indicate that the HOXA1-induced gene signature successfully categorizes melanoma specimens based on their metastatic potential and, importantly, is capable of stratifying melanoma patient risk for metastasis based on expression in primary tumors.

6

Wardwell-Ozgo J, Dogruluk T, Gifford A, Zhang Y, Heffernan TP, van Doorn R, Creighton CJ, Chin L, Scott KL