PHD1 regulates p53-mediated colorectal cancer chemoresistance

Deschoemaeker, S. et al. (2015) PHD1 regulates p53-mediated colorectal cancer chemoresistance. EMBO Molecular Medicine, 7(10), pp. 1350-65. (doi:10.15252/emmm.201505492) (PMID:26290450) (PMCID:PMC4604688)

Deschoemaeker, S. et al. (2015) PHD1 regulates p53-mediated colorectal cancer chemoresistance. EMBO Molecular Medicine, 7(10), pp. 1350-65. (doi:10.15252/emmm.201505492) (PMID:26290450) (PMCID:PMC4604688)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lilla, Dr Sergio and Zanivan, Dr Sara Rossana and Maddocks, Dr Oliver and Vousden, Karen
Authors: Deschoemaeker, S., Di Conza, G., Lilla, S., Martín-Pérez, R., Mennerich, D., Boon, L., Hendrikx, S., Maddocks, O. D.K., Marx, C., Radhakrishnan, P., Prenen, H., Schneider, M., Myllyharju, J., Kietzmann, T., Vousden, K. H., Zanivan, S., and Mazzone, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:EMBO Molecular Medicine
Publisher:Wiley
ISSN:1757-4676
ISSN (Online):1757-4684
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in EMBO Molecular Medicine 7(10):1350-1365
Publisher Policy:Reproduced under a Creative Commons License

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