title: Loss of PHD3 allows tumours to overcome hypoxic growth inhibition and sustain proliferation through EGFR.
abstract: Solid tumours are exposed to microenvironmental factors such as hypoxia that normally inhibit cell growth. However, tumour cells are capable of counteracting these signals through mechanisms that are largely unknown. Here we show that the prolyl hydroxylase PHD3 restrains tumour growth in response to microenvironmental cues through the control of EGFR. PHD3 silencing in human gliomas or genetic deletion in a murine high-grade astrocytoma model markedly promotes tumour growth and the ability of tumours to continue growing under unfavourable conditions. The growth-suppressive function of PHD3 is independent of the established PHD3 targets HIF and NF-κB and its hydroxylase activity. Instead, loss of PHD3 results in hyperphosphorylation of epidermal growth factor receptor (EGFR). Importantly, epigenetic/genetic silencing of PHD3 preferentially occurs in gliomas without EGFR amplification. Our findings reveal that PHD3 inactivation provides an alternative route of EGFR activation through which tumour cells sustain proliferative signalling even under conditions of limited oxygen availability.
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Anne-Theres
authors.initials: AT
authors.lastname: Henze
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Boyan K
authors.initials: BK
authors.lastname: Garvalov
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Seidel
authors.affiliation: 1] Institute of Cell Biology and Neuroscience, Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt, Germany [2] Focus Program Translational Neurosciences (FTN), University of Mainz, 55131 Mainz, Germany.
authors.forename: Angel M
authors.initials: AM
authors.lastname: Cuesta
authors.affiliation: 1] Institute of Cell Biology and Neuroscience, Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt, Germany [2] Focus Program Translational Neurosciences (FTN), University of Mainz, 55131 Mainz, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Ritter
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Filatova
authors.affiliation: 1] Institute of Cell Biology and Neuroscience, Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt, Germany [2] Focus Program Translational Neurosciences (FTN), University of Mainz, 55131 Mainz, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Foss
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Higinio
authors.initials: H
authors.lastname: Dopeso
authors.affiliation: Institute of Cell Biology and Neuroscience, Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt, Germany.
authors.forename: Clara L
authors.initials: CL
authors.lastname: Essmann
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.affiliation: Institute of Neuropathology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.affiliation: Vesalius Research Center (VRC), Angiogenesis and Neurovascular Link Laboratory, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: 1] Institute of Cell Biology and Neuroscience, Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, 60438 Frankfurt, Germany [2] Focus Program Translational Neurosciences (FTN), University of Mainz, 55131 Mainz, Germany.
authors.forename: Amparo
authors.initials: A
authors.lastname: Acker-Palmer
authors.affiliation: Institute of Neuropathology, University of Giessen, 35392 Giessen, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Acker
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055786:Gene Knockout Techniques; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D000860:Hypoxia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000172:deficiency / Q000235:genetics*; D008297:Male; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency / Q000235:genetics*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C522722:PHD3 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D010100:Oxygen