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

• Published in: Cell death & disease Vol. 5; no. 7; p. e1322
• Main Authors: Sun, W, Jelkmann, W, Depping, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.07.2014; Nature Publishing Group
• Subjects: 631/208/199; 631/67/1922; 631/80/82; 631/80/86; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Death; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Glioblastoma - enzymology; Glioblastoma - genetics; Glioblastoma - physiopathology; Humans; Hypoxia - enzymology; Hypoxia - genetics; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunology; Life Sciences; Original; original-article; Oxygen - metabolism; Prolyl Hydroxylases - genetics; Prolyl Hydroxylases - metabolism; Up-Regulation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.295

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-1 α , -2 α ) 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-1 α and HIF-2 α by interacting with other intracellular molecules. In this study, we found that in the glioblastoma cells, PHD2 maintains the gene expression of HIF-1 α in dependence of nuclear factor κ B and suppresses the gene expression of HIF-2 α through HIF-1 α . The PHD2-mediated degradation of HIF-1 α and HIF-2 α 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.