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

• Published in: Nucleic acids research Vol. 43; no. 10; pp. 5081 - 5098
• Main Authors: Liu, Xing, Chen, Zhu, Xu, Chenxi, Leng, Xiaoqian, Cao, Hong, Ouyang, Gang, Xiao, Wuhan
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 26.05.2015
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Hypoxia; Cell Line; Cells, Cultured; Gene Expression Regulation; Glucose - metabolism; Histone-Lysine N-Methyltransferase - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - chemistry; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Lysine - metabolism; Methylation; Mice; Molecular Biology; Signal Transduction; Transcription, Genetic
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkv379

Hypoxia-inducible factor (HIF)-1α and HIF-2α are the main regulators of cellular responses to hypoxia. Post-translational modifications of HIF-1α and 2α 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-1α at lysine 32 and HIF-2α at lysine K29; this methylation inhibits the expression of HIF-1α/2α targets by impairing the occupancy of HIF-α 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-1α/2α 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-1α/2α and demonstrate that Set7-medited lysine methylation negatively regulates HIF-α transcriptional activity and HIF-1α-mediated glucose homeostasis.