To test whether the interplay between VHL and RAPTOR in our system was HIF-dependent, ccRCC cells were treated with the HIF2α isoform specific inhibitor PT238526.Treatment of RCC4 and 786-O cells with PT2385 significantly reduced HIF2α activity, as evidenced by decreased expression of the target gene PAI-116,27, but did not alter RAPTOR protein levels or mRNA expression (Fig. 3g,h, and Supplementary Fig. 3d,e). This evidence concerns the gene EPAS1 and nonpapillary renal cell carcinoma.