Hypoxia-induced HIF1α targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis

Hypoxia and HIF1 alpha signaling direct tissue-specific gene responses regulating tumor progression, invasion, and metastasis. By integrating HIF1 alpha knockdown and hypoxia-induced gene expression changes, this study identifies a melanocyte-specific, HIF1 alpha-dependent/hypoxia-responsive gene expression signature. Integration of these gene expression changes with HIF1 alpha ChIP-Seq analysis identifies 81 HIF1 alpha direct target genes in melanocytes. The expression levels for 10 of the HIF1 alpha direct targets -GAPDH, PKM, PPAT, DARS, DTWD1, SEH1L, ZNF292, RLF, AGTRAP, and GPC6 -are significantly correlated with reduced time of disease-free status in melanoma by logistic regression (P-value = 0.0013) and ROC curve analysis (AUC = 0.826, P-value < 0.0001). This HIF1 alpha-regulated profile defines a melanocyte-specific response under hypoxia, and demonstrates the role of HIF1 alpha as an invasive cell state gatekeeper in regulating cellular metabolism, chromatin and transcriptional regulation, vascularization, and invasion.