Hypoxia also upregulated Sphk1 mRNA expression in endothelial cells [45] and cancer cells [46], and this was mediated by the transcription factors HIF-1α and HIF-2α, which can bind to one of the two hypoxia response elements (HREs) identified in the human Sphk1 promoter region [45]. Here, EPAS1 is linked to cancer.