To confirm a causal relationship between the loss of Phd2 and the elevation in Akt pathway activity, we re-expressed Phd2 in the BrafV600E; Phd2−/− melanoma cells and found that re-expression of Phd2 in these cells induced a significant decrease in HIF-1α and HIF-2α protein expression and a decrease in the phosphorylation of Akt and 4EBP1 compared to those of control (Fig. 6c). Here, EPAS1 is linked to melanoma.