Further supporting ERK1/2 regulation of HIF-2α, HIF-2α is directly phosphorylated by ERK1/2 in human hepatoma cells, and MEK inhibition upstream of ERK shifts hypoxia-stabilized nuclear-localized HIF-2α protein to the cytoplasm reducing HIF-2α-mediated gene expression [79]. The gene discussed is EPAS1; the disease is hepatocellular carcinoma.