Hypoxia‐induced HIF 1 α targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis

Summary Hypoxia and HIF 1 α signaling direct tissue‐specific gene responses regulating tumor progression, invasion, and metastasis. By integrating HIF 1 α knockdown and hypoxia‐induced gene expression changes, this study identifies a melanocyte‐specific, HIF 1 α ‐dependent/hypoxia‐responsive gene expression signature. Integration of these gene expression changes with HIF 1 α Ch IP ‐Seq analysis identifies 81 HIF 1 α direct target genes in melanocytes. The expression levels for 10 of the HIF 1 α direct targets – GAPDH , PKM , PPAT , DARS , DTWD 1 , SEH 1L , ZNF 292 , RLF , AGTRAP , and GPC 6 – 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 HIF 1 α ‐regulated profile defines a melanocyte‐specific response under hypoxia, and demonstrates the role of HIF 1 α as an invasive cell state gatekeeper in regulating cellular metabolism, chromatin and transcriptional regulation, vascularization, and invasion.