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 oxygenlabile 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-a 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 jB 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.
Originalsprache | Englisch |
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Aufsatznummer | e1322 |
Zeitschrift | Cell Death and Disease |
Jahrgang | 5 |
Ausgabenummer | 7 |
DOIs | |
Publikationsstatus | Veröffentlicht - 07.2014 |
Strategische Forschungsbereiche und Zentren
- Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)