Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation

Hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha are the main regulators of cellular responses to hypoxia. Post-translational modifications of HIF-1 alpha and 2 alpha are necessary to modulate their functions. The methylation of non-histone proteins by Set7, an SET domain-containing lysine methyltransferase, is a novel regulatory mechanism to control cell protein function in response to various cellular stresses. In this study, we show that Set7 methylates HIF-1 alpha at lysine 32 and HIF-2 alpha at lysine K29; this methylation inhibits the expression of HIF-1 alpha/2 alpha targets by impairing the occupancy of HIF-alpha on hypoxia response element of HIF target gene promoter. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 exhibit upregulated HIF target genes. Set7 inhibitor blocks HIF-1 alpha/2 alpha methylation to enhance HIF target gene expression. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 or inhibition of Set7 by the inhibitor subjected to hypoxia display an increased glucose uptake and intracellular adenosine triphosphate levels. These findings define a novel modification of HIF-1 alpha/2 alpha and demonstrate that Set7-medited lysine methylation negatively regulates HIF-alpha transcriptional activity and HIF-1 alpha-mediated glucose homeostasis.