title: Prolyl-4-hydroxylase 2 enhances hypoxia-induced glioblastoma cell death by regulating the gene expression of hypoxia-inducible factor-α.
abstract: Oxygen deprivation (hypoxia) is a common feature of solid tumors in advanced stages. The primary cellular transcriptional responses to hypoxia are mainly mediated by the transcription factor hypoxia-inducible factor (HIF). HIF consists of an oxygen-labile α-subunit (HIF-1α, -2α) and a stable β-subunit (ARNT). Prolyl-4-hydroxylase 2 (PHD2) is known as an important mediator of the oxygen-dependent degradation of HIF-α subunits. As HIF-α subunits are not confirmed to be the only substrates of PHD2, it is unknown whether PHD2 regulates HIF-1α and HIF-2α by interacting with other intracellular molecules. In this study, we found that in the glioblastoma cells, PHD2 maintains the gene expression of HIF-1α in dependence of nuclear factor κB and suppresses the gene expression of HIF-2α through HIF-1α. The PHD2-mediated degradation of HIF-1α and HIF-2α seems less important. Furthermore, PHD2 enhances hypoxia-induced glioblastoma cell death by modulating the expression of the HIF target genes glucose transporter 1, vascular endothelial growth factor-A and Bcl-2 binding protein 3. Our findings show that PHD2 inhibits the adaptation of glioblastoma cells to hypoxia by regulating the HIF-α subunits in a non-canonical way. Modulation of PHD2 activity might be considered as a new way to inhibit glioblastoma progression.
authors.affiliation: Institute of Physiology, Center for Structural and Cell Biology in Medicine, University of Luebeck, Luebeck, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Sun
authors.affiliation: Institute of Physiology, Center for Structural and Cell Biology in Medicine, University of Luebeck, Luebeck, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Jelkmann
authors.affiliation: Institute of Physiology, Center for Structural and Cell Biology in Medicine, University of Luebeck, Luebeck, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Depping
mesh_terms: D016923:Cell Death; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D000860:Hypoxia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D064828:Prolyl Hydroxylases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064828:Prolyl Hydroxylases; D010100:Oxygen