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PHD1 regulates p53-mediated colorectal cancer chemoresistance

Sofie Deschoemaeker1, Giusy Di Conza1, Sergio Lilla2

  • 1Lab of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium Lab of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.

EMBO Molecular Medicine
|August 21, 2015
PubMed

Insights

Silencing prolyl hydroxylase domain protein 1 (PHD1) prevents colorectal cancer cell survival after chemotherapy by inhibiting DNA repair. Targeting PHD1 may overcome chemotherapy resistance in colorectal cancer (CRC).

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Chemotherapy resistance is a significant obstacle in colorectal cancer (CRC) treatment.
  • The molecular mechanisms driving CRC chemoresistance are not fully understood.

Purpose of the Study:

  • To investigate the role of prolyl hydroxylase domain (PHD) proteins in colorectal cancer (CRC) chemotherapy resistance.
  • To elucidate the molecular mechanisms by which PHD proteins influence p53 activation and DNA repair in CRC cells.

Main Methods:

  • Utilized gene silencing techniques (knockdown) to inhibit PHD1, PHD2, and PHD3 expression in CRC cell lines.
  • Assessed p53 activation, DNA repair capacity, and apoptosis following chemotherapy treatment.
  • Investigated the interaction between p53 and p38α kinase using biochemical assays.
  • Evaluated the effect of PHD1 knockdown on CRC sensitivity to 5-fluorouracil (5-FU) in a mouse model.

Main Results:

  • Silencing PHD1, but not PHD2 or PHD3, inhibited p53 activation in CRC cells treated with chemotherapy.
  • PHD1 activity was found to be crucial for p53 binding to p38α kinase in a hydroxylation-dependent manner.
  • Activated p53, through phosphorylation at serine 15, facilitates nucleotide excision repair by interacting with XPB, thus promoting cell survival.
  • PHD1 knockdown significantly sensitized CRC tumors to 5-FU chemotherapy in vivo.

Conclusions:

  • PHD1 plays a critical role in mediating resistance to chemotherapy in colorectal cancer (CRC) by regulating p53 activation and DNA repair.
  • PHD1 is identified as a potential therapeutic target for overcoming chemoresistance in CRC.
  • Development of PHD1-specific inhibitors for combination therapy with conventional chemotherapy warrants further investigation.
Keywords:
DNA repairchemotherapy resistancecolorectal cancerprolyl hydroxylase domain proteinstumor suppressor p53

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