We find that, in additional to inhibiting hypoxia-inducible factor 2α (HIF2α), a major oncogenic driver in Von Hippel-Lindau (VHL)−/− ccRCC, YAP also blocks nuclear factor κB (NF-κB ) signaling in ccRCC to inhibit cancer cell growth under conditions where HIF2α is dispensable. Here, EPAS1 is linked to cancer.