University of Oulu

Deschoemaeker, Sofie et al. (2015) PHD1 regulates p53‐mediated colorectal cancer chemoresistance. EMBO Molecular Medicine (2015) 7, 1350-1365. http://dx.doi.org/10.15252/emmm.201505492

PHD1 regulates p53‐mediated colorectal cancer chemoresistance

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Author: Deschoemaeker, Sofie1,2; Di Conza, Giusy1,2; Lilla, Sergio3;
Organizations: 1Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium
2Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium
3Cancer Research UK Beatson Institute, Glasgow, UK
4Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland
5Department of Biochemistry, Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Friedrich Schiller University of Jena, Jena, Germany
6Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
7Digestive Oncology Department, University Hospitals Leuven, Leuven, Belgium
8Oulu Center for Cell‐Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.4 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe201703142174
Language: English
Published: EMBO, 2015
Publish Date: 2017-03-14
Description:

Abstract

Overcoming resistance to chemotherapy is a major challenge in colorectal cancer (CRC) treatment, especially since the underlying molecular mechanisms remain unclear. We show that silencing of the prolyl hydroxylase domain protein PHD1, but not PHD2 or PHD3, prevents p53 activation upon chemotherapy in different CRC cell lines, thereby inhibiting DNA repair and favoring cell death. Mechanistically, PHD1 activity reinforces p53 binding to p38α kinase in a hydroxylation‐dependent manner. Following p53–p38α interaction and chemotherapeutic damage, p53 can be phosphorylated at serine 15 and thus activated. Active p53 allows nucleotide excision repair by interacting with the DNA helicase XPB, thereby protecting from chemotherapy‐induced apoptosis. In accord with this observation, PHD1 knockdown greatly sensitizes CRC to 5‐FU in mice. We propose that PHD1 is part of the resistance machinery in CRC, supporting rational drug design of PHD1‐specific inhibitors and their use in combination with chemotherapy.

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Series: EMBO molecular medicine
ISSN: 1757-4684
ISSN-E: 1757-4684
ISSN-L: 1757-4684
Volume: 7
Issue: 10
Pages: 1245 - 1384
DOI: 10.15252/emmm.201505492
OADOI: https://oadoi.org/10.15252/emmm.201505492
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
Subjects:
Funding: This work was supported by grants from FWO (1.5.056.11.N.00; www.fwo.be) and Stichting tegen Kanker (2010‐169 and 2012‐208; www.kanker.be). S.D is supported by Vlaamse Liga tegen Kanker (www.tegenkanker.be). H.P is supported by Stichting tegen kanker (2014‐082; www.kanker.be). M.M is supported by an ERC Starting Grant (OxyMO; www.erc.europa.eu). S.L, S.Z, O.M, and K.V are supported by Cancer Research UK.
Copyright information: © 2015 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
  https://creativecommons.org/licenses/by/4.0/