title: Prolyl hydroxylases 2 and 3 act in gliomas as protective negative feedback regulators of hypoxia-inducible factors.
abstract: Adaptive responses to hypoxia in tumors are transcriptionally regulated by the hypoxia inducible factors (HIF-1alpha/HIF-2alpha), which are tightly controlled by the HIF-prolyl hydroxylases (PHD). Hypoxia induces expression of the PHD2 and PHD3 proteins in tumors but the pathobiological significance of these events is uncertain. Here, we show that PHD2 and PHD3 induction acts within a negative feedback loop to limit the hypoxic HIF response. In glioblastomas, PHD2 and PHD3 are hypoxia-inducible in vitro and expressed in hypoxic areas of tumors in vivo. Comparison with other PHDs revealed distinct cytoplasmatic and nuclear localization patterns of PHD2 and PHD3. Gain and loss of function experiments defined PHD2 and PHD3 as HIF target genes that remained operative even at low oxygen concentrations. We found that increased PHD levels could compensate for reduced oxygen availability to regulate the HIF response. This negative feedback loop protected tumor cells against hypoxia-induced cell death, functionally implicating this pathway in the control of the tumor-suppressive components of the HIF system in glioblastoma. Moreover, PHD inhibition facilitated cell death induction by staurosporine or tumor necrosis factor-related apoptosis-inducing ligand, hinting at a more general protective role of PHD in the regulation of cell viability. In summary, our findings recognize the PHD/HIF regulatory axis as a novel therapeutic target to disable a tumor's ability to adjust to hypoxic conditions and control cell survival, helping to potentially overcome therapeutic cell death resistance in glioblastomas.
authors.affiliation: Institute of Neuropathology, Giessen, Germany.
authors.forename: Anne-Theres
authors.initials: AT
authors.lastname: Henze
authors.forename: Johanna
authors.initials: J
authors.lastname: Riedel
authors.forename: Tanja
authors.initials: T
authors.lastname: Diem
authors.forename: Julia
authors.initials: J
authors.lastname: Wenner
authors.forename: Ingo
authors.initials: I
authors.lastname: Flamme
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouyseggur
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.forename: Till
authors.initials: T
authors.lastname: Acker
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049308:Dioxygenases / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D049308:Dioxygenases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D011393:Procollagen-Proline Dioxygenase; D000099162:Endothelial PAS Domain-Containing Protein 1; C490190:EGLN1 protein, human; C488894:EGLN3 protein, human