PLD activity (peaking at 15–30 min) is known to regulate HIF-2α accumulation in ccRCC,61 but a novel finding is that SphK1 is a downstream target of PLD under hypoxia as described earlier in different physiological settings.36, 62 Using A498 and 786-O VHL-defective cells that only express HIF-2α, we demonstrate that SphK1 activity controls not only HIF-2α protein content but also its transcriptional activity, as downregulation of specific HIF-2-regulated genes such as GLUT-1 or cyclin D1 was observed in SphK1-silenced cells. Here, VHL is linked to nonpapillary renal cell carcinoma.