Giusy Di Conza, Sarah Trusso Cafarello, Stefan Loroch, Daniela Mennerich, Sofie Deschoemaeker, Mario Di Matteo, Manuel Ehling, Kris Gevaert, Hans Prenen, Rene Peiman Zahedi, Albert Sickmann, Thomas Kietzmann, Fabiola Moretti, Massimiliano Mazzone, The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia, Cell Reports, Volume 18, Issue 7, 14 February 2017, Pages 1699-1712, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2017.01.051.
The mTOR and PP2A pathways regulate PHD2 phosphorylation to fine-tune HIF1α levels and colorectal cancer cell survival under hypoxia
|Author:||Di Conza , Giusy1,2; Trusso Cafarello, Sarah1,2; Loroch, Stefan3;|
1Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, 3000 Leuven, Belgium
2Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Center for Cancer Biology, KU Leuven, 3000 Leuven, Belgium
3Leibniz Institut für Analytische Wissenschaften - ISAS - e.V., 44227 Dortmund, Germany
4Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90220 Oulu, Finland
5Biocenter Oulu, University of Oulu, 90220 Oulu, Finland
6Department of Medical Protein Research, VIB, 9000 Ghent, Belgium
7Department of Biochemistry, Ghent University, 9000 Ghent, Belgium
8Digestive Oncology Unit, Department of Oncology, University Hospital Gasthuisberg, KU Leuven, 3000 Leuven, Belgium
9Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen AB24 3UE, Scotland, UK
10Medizinisches Proteom Center, Ruhr Universität Bochum, 44801 Bochum, Germany
11Institute of Cell Biology and Neurobiology, National Research Council of Italy, 00143 Roma, Italy
|Online Access:||PDF Full Text (PDF, 4.1 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe201706277486
|Publish Date:|| 2017-06-27
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.
|Pages:||1699 - 1712|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work was supported by grants from ERANET (OxyUC, G0D8115N), FWO (1505611N00), Stichting Tegen Kanker (2010-169), Bundesministerium für Bildung und Forschung, and the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen. G.D.C. is supported by a Pegasus FWO-Marie Curie fellowship (1211413N), M.E. by DFG (EH 472/1-1), and S.D. by VLK (EVDS and 419.052.173). M.M. received an ERC starting grant (OxyMO, 308459).
© 2017 The Author(s).This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).