We previously identified SphK1/S1P signaling as a new modulator of HIF-1α and HIF-2α activities under hypoxia in a wide array of cancer cell models (prostate, glioma, breast, lung and renal cell carcinoma) both in vitro and in vivo [25,26,27]. Here, SPHK1 is linked to hereditary clear cell renal cell carcinoma.