PMID- 28199842 OWN - NLM STAT- MEDLINE DCOM- 20171127 LR - 20211204 IS - 2211-1247 (Electronic) VI - 18 IP - 7 DP - 2017 Feb 14 TI - The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1alpha Levels and Colorectal Cancer Cell Survival under Hypoxia. PG - 1699-1712 LID - S2211-1247(17)30108-0 [pii] LID - 10.1016/j.celrep.2017.01.051 [doi] AB - Oxygen-dependent HIF1alpha hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1alpha 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 HIF1alpha. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55alpha, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1alpha accumulation. These events promote autophagy-mediated cell survival in colorectal cancer (CRC) cells. B55alpha 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, B55alpha, and HIF1alpha 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. CI - Copyright (c) 2017 The Author(s). Published by Elsevier Inc. All rights reserved. FAU - Di Conza, Giusy AU - Di Conza G AD - 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. FAU - Trusso Cafarello, Sarah AU - Trusso Cafarello S AD - 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. FAU - Loroch, Stefan AU - Loroch S AD - Leibniz Institut fur Analytische Wissenschaften - ISAS - e.V., 44227 Dortmund, Germany. FAU - Mennerich, Daniela AU - Mennerich D AD - Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, 90220 Oulu, Finland. FAU - Deschoemaeker, Sofie AU - Deschoemaeker S AD - 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. FAU - Di Matteo, Mario AU - Di Matteo M AD - 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. FAU - Ehling, Manuel AU - Ehling M AD - 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. FAU - Gevaert, Kris AU - Gevaert K AD - Department of Medical Protein Research, VIB, 9000 Ghent, Belgium; Department of Biochemistry, Ghent University, 9000 Ghent, Belgium. FAU - Prenen, Hans AU - Prenen H AD - Digestive Oncology Unit, Department of Oncology, University Hospital Gasthuisberg, KU Leuven, 3000 Leuven, Belgium. FAU - Zahedi, Rene Peiman AU - Zahedi RP AD - Leibniz Institut fur Analytische Wissenschaften - ISAS - e.V., 44227 Dortmund, Germany. FAU - Sickmann, Albert AU - Sickmann A AD - Leibniz Institut fur 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 Universitat Bochum, 44801 Bochum, Germany. FAU - Kietzmann, Thomas AU - Kietzmann T AD - Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, 90220 Oulu, Finland. FAU - Moretti, Fabiola AU - Moretti F AD - Institute of Cell Biology and Neurobiology, National Research Council of Italy, 00143 Roma, Italy. FAU - Mazzone, Massimiliano AU - Mazzone M AD - 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. LA - eng PT - Journal Article PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (HIF1A protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - EC 1.14.11.2 (EGLN1 protein, human) RN - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.3.16 (Protein Phosphatase 2) SB - IM MH - Cell Hypoxia/*physiology MH - Cell Line MH - Cell Line, Tumor MH - Cell Proliferation/physiology MH - Cell Survival/*physiology MH - Colorectal Neoplasms/*metabolism MH - HEK293 Cells MH - HT29 Cells MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism MH - Hypoxia-Inducible Factor-Proline Dioxygenases/*metabolism MH - Phosphorylation/physiology MH - Protein Phosphatase 2/*metabolism MH - Ribosomal Protein S6 Kinases, 70-kDa/metabolism MH - Signal Transduction/physiology MH - TOR Serine-Threonine Kinases/*metabolism PMC - PMC5318657 EDAT- 2017/02/16 06:00 MHDA- 2017/11/29 06:00 PMCR- 2017/02/14 CRDT- 2017/02/16 06:00 PHST- 2014/11/25 00:00 [received] PHST- 2016/10/22 00:00 [revised] PHST- 2017/01/19 00:00 [accepted] PHST- 2017/02/16 06:00 [entrez] PHST- 2017/02/16 06:00 [pubmed] PHST- 2017/11/29 06:00 [medline] PHST- 2017/02/14 00:00 [pmc-release] AID - S2211-1247(17)30108-0 [pii] AID - 10.1016/j.celrep.2017.01.051 [doi] PST - ppublish SO - Cell Rep. 2017 Feb 14;18(7):1699-1712. doi: 10.1016/j.celrep.2017.01.051.