PHD1 regulates p53-mediated colorectal cancer chemoresistance.
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.
Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.
Sofie
S
Deschoemaeker
Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.
Giusy
G
Di Conza
Cancer Research UK Beatson Institute, Glasgow, UK.
Sergio
S
Lilla
Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.
Rosa
R
Martín-Pérez
Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland.
Daniela
D
Mennerich
Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.
Lise
L
Boon
Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.
Stefanie
S
Hendrikx
Cancer Research UK Beatson Institute, Glasgow, UK.
Oliver D K
OD
Maddocks
Cancer Research UK Beatson Institute, Glasgow, UK Department of Biochemistry, Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Friedrich Schiller University of Jena, Jena, Germany.
Christian
C
Marx
Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
Praveen
P
Radhakrishnan
Digestive Oncology Department, University Hospitals Leuven, Leuven, Belgium.
Hans
H
Prenen
Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
Martin
M
Schneider
Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
Johanna
J
Myllyharju
Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland.
Thomas
T
Kietzmann
Cancer Research UK Beatson Institute, Glasgow, UK.
Karen H
KH
Vousden
Cancer Research UK Beatson Institute, Glasgow, UK.
Sara
S
Zanivan
Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium massimiliano.mazzone@vib-kuleuven.be.
Massimiliano
M
Mazzone
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D059248:Chemoradiotherapy; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D010766:Phosphorylation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; C490190:EGLN1 protein, human; C447780:EGLN2 protein, human; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D048308:Mitogen-Activated Protein Kinase 14; D005472:Fluorouracil
DNA repair; chemotherapy resistance; colorectal cancer; prolyl hydroxylase domain proteins; tumor suppressor p53