Here, we report that the SphK1/S1P signaling pathway may act as a canonical regulator of HIF-2α expression in multiple cancer cell lineages (lung, prostate and glioma) as well as in ccRCC cell lines (CAKI-1, A498 and 786-O) representing the sub-groups found in human clinic. The gene discussed is SPHK1; the disease is nonpapillary renal cell carcinoma.