title: Functional regulation of hypoxia inducible factor-1α by SET9 lysine methyltransferase.
abstract: HIF-1α is degraded by oxygen-dependent mechanisms but stabilized in hypoxia to form transcriptional complex HIF-1, which transactivates genes promoting cancer hallmarks. However, how HIF-1α is specifically regulated in hypoxia is poorly understood. Here, we report that the histone methyltransferase SET9 promotes HIF-1α protein stability in hypoxia and enhances HIF-1 mediated glycolytic gene transcription, thereby playing an important role in mediating cancer cell adaptation and survival to hypoxic stress. Specifically, SET9 interacts with HIF-1α and promotes HIF-1α protein stability in hypoxia. Silencing SET9 by siRNA reduces HIF-1α protein stability in hypoxia, and attenuates the hypoxic induction of HIF-1 target genes mediating hypoxic glycolysis. Mechanistically, we find that SET9 is enriched at the hypoxia response elements (HRE) within promoters of the HIF-1-responsive glycolytic genes. Silencing SET9 reduces HIF-1α levels at these HREs in hypoxia, thereby attenuating HIF-1-mediated gene transcription. Further, silencing SET9 by siRNA reduces hypoxia-induced glycolysis and inhibits cell viability of hypoxic cancer cells. Our findings suggest that SET9 enriches at HRE sites of HIF-1 responsive glycolytic genes and stabilizes HIF-1α at these sites in hypoxia, thus establishes an epigenetic mechanism of the metabolic adaptation in hypoxic cancer cells.
authors: Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors: Qiong
authors: Q
authors: Liu
authors: Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors: Hao
authors: H
authors: Geng
authors: Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors: Changhui
authors: C
authors: Xue
authors: Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors: Tomasz M
authors: TM
authors: Beer
authors: Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. Electronic address: qianzh@ohsu.edu.
authors: David Z
authors: DZ
authors: Qian
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D019610:Cytoprotection; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006019:Glycolysis / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D020218:Response Elements / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D002843:Chromatin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; D046988:Proteasome Endopeptidase Complex; D008239:Lysine
keywords: Cancer; Gene regulation; Hypoxia; Metabolic adaptation; Protein interaction; Transcription factor
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