PHD1 regulates p53‐mediated colorectal cancer chemoresistance

EMBO Molecular Medicine

Sofie Deschoemaeker²  Giusy Di Conza²  Sergio Lilla⁴  Rosa Martín-Pérez²  Daniela Mennerich⁶  Lise Boon²  Stefanie Hendrikx²  Oliver DK Maddocks⁴  Christian Marx⁴  Praveen Radhakrishnan¹  Hans Prenen³  Martin Schneider¹  Johanna Myllyharju⁵  Thomas Kietzmann⁶  Karen H Vousden⁴  Sara Zanivan⁴ 

[1] Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany;Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium;Digestive Oncology Department, University Hospitals Leuven, Leuven, Belgium;Cancer Research UK Beatson Institute, Glasgow, UK;Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland;Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland

关键词: chemotherapy resistance;    colorectal cancer;    DNA repair;    prolyl hydroxylase domain proteins;    tumor suppressor p53;   

DOI  :  10.15252/emmm.201505492

来源: Wiley

【 摘 要 】

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.

Synopsis

Resistance to the commonly used chemotherapeutic drugs 5-FU, irinotecan and oxaliplatin in colorectal cancer remains a major clinical problem. Here, it is shown that PHD1 (EGLN2) can cause resistance to chemotherapy through the regulation of p53-mediated DNA repair.

• Chemotherapy (5-FU) effectiveness was improved upon silencing of PHD1 in a xenograft colorectal cancer model.
• p38α-mediated p53 phosphorylation upon chemotherapy was facilitated by PHD1 prolyl hydroxylase function and interaction with p53.
• The interaction of p53 with the nucleotide excision repair component XPB and thus DNA repair upon chemotherapy-induced damage was blocked by the reduction of p53 phosphorylation at Ser15.
• DNA contact mutant p53 (R248) can still be modulated by PHD1 and regulate DNA repair.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.