title: The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia.
abstract: Oxygen-dependent HIF1α hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1α partly escapes degradation because of low oxygen availability. Here, we show that PHD2 is phosphorylated on serine 125 (S125) by the mechanistic target of rapamycin (mTOR) downstream kinase P70S6K and that this phosphorylation increases its ability to degrade HIF1α. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55α, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1α accumulation. These events promote autophagy-mediated cell survival in colorectal cancer (CRC) cells. B55α knockdown blocks neoplastic growth of CRC cells in vitro and in vivo in a PHD2-dependent manner. In patients, CRC tissue expresses higher levels of REDD1, B55α, and HIF1α but has lower phospho-S125 PHD2 compared with a healthy colon. Our data disclose a mechanism of PHD2 regulation that involves the mTOR and PP2A pathways and controls tumor growth.
authors.affiliation: Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer Biology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Giusy
authors.initials: G
authors.lastname: Di Conza
authors.affiliation: Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer Biology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Trusso Cafarello
authors.affiliation: Leibniz Institut für Analytische Wissenschaften - ISAS - e.V., 44227 Dortmund, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Loroch
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, 90220 Oulu, Finland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Mennerich
authors.affiliation: Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer Biology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Deschoemaeker
authors.affiliation: Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer Biology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Mario
authors.initials: M
authors.lastname: Di Matteo
authors.affiliation: Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer Biology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ehling
authors.affiliation: Department of Medical Protein Research, VIB, 9000 Ghent, Belgium; Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.affiliation: Digestive Oncology Unit, Department of Oncology, University Hospital Gasthuisberg, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Prenen
authors.affiliation: Leibniz Institut für Analytische Wissenschaften - ISAS - e.V., 44227 Dortmund, Germany.
authors.forename: Rene Peiman
authors.initials: RP
authors.lastname: Zahedi
authors.affiliation: Leibniz Institut für Analytische Wissenschaften - ISAS - e.V., 44227 Dortmund, Germany; Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen AB24 3UE, Scotland, UK; Medizinisches Proteom Center, Ruhr Universität Bochum, 44801 Bochum, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Sickmann
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, 90220 Oulu, Finland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kietzmann
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council of Italy, 00143 Roma, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Moretti
authors.affiliation: Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, 3000 Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer Biology, KU Leuven, 3000 Leuven, Belgium. Electronic address: massimiliano.mazzone@vib-kuleuven.be.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D054648:Protein Phosphatase 2