Prolyl-4-hydroxylase 2 enhances hypoxia-induced glioblastoma cell death by regulating the gene expression of hypoxia-inducible factor-α

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 alpha-subunit (HIF-1 alpha, -2 alpha) and a stable beta-subunit (ARNT). Prolyl-4-hydroxylase 2 (PHD2) is known as an important mediator of the oxygen-dependent degradation of HIF-alpha subunits. As HIF-alpha subunits are not confirmed to be the only substrates of PHD2, it is unknown whether PHD2 regulates HIF-1 alpha and HIF-2 alpha by interacting with other intracellular molecules. In this study, we found that in the glioblastoma cells, PHD2 maintains the gene expression of HIF-1 alpha in dependence of nuclear factor KB and suppresses the gene expression of HIF-2 alpha through HIF-1 alpha. The PHD2-mediated degradation of HIF-1 alpha and HIF-2 alpha 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-alpha subunits in a non-canonical way. Modulation of PHD2 activity might be considered as a new way to inhibit glioblastoma progression.