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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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P53 represses pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD) expression in response to thymidylate

Prashanth Gokare1,2, Niklas K Finnberg1, Phillip H Abbosh1

  • 1Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Scientific Reports
|August 31, 2017
PubMed

Insights

The tumor suppressor p53 controls pyrimidine metabolism by repressing dihydropyrimidine dehydrogenase (DPYD) expression. This p53-DPYD regulation impacts 5-fluorouracil (5-FU) chemotherapy efficacy and toxicity.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Pharmacology

Background:

  • Nucleotide metabolism is crucial for cancer cell proliferation and drug resistance.
  • Dihydropyrimidine dehydrogenase (DPYD) is a key enzyme in pyrimidine catabolism, affecting chemotherapy response.
  • The tumor suppressor protein p53 plays a role in cellular stress responses.

Purpose of the Study:

  • To investigate the role of p53 in regulating DPYD expression.
  • To determine the impact of p53-mediated DPYD control on 5-fluorouracil (5-FU) pharmacokinetics and therapeutic efficacy.
  • To elucidate the molecular mechanisms underlying p53's regulation of DPYD.

Main Methods:

  • In silico analysis and chromatin-immunoprecipitation (ChIP) to identify p53 binding sites.
  • Analysis of histone modifications (H3K9AC, H3K27me3) at the DPYD promoter.
  • Assessment of DPYD mRNA and protein expression.
  • In vivo studies using liver-specific Tp53 knockout mice and a colorectal tumor model.
  • Investigating the roles of DNA-PK and ATM signaling pathways.

Main Results:

  • A conserved p53 DNA-binding site downstream of the DPYD gene was identified, with increased p53 occupancy after 5-FU treatment.
  • p53 represses DPYD expression in a p53-dependent manner, indicated by reduced mRNA and protein levels and altered histone marks.
  • DPYD repression by p53 is enhanced by thymidylate synthase inhibition and involves DNA-PK and ATM signaling.
  • Loss of p53 in vivo leads to increased 5-FU catabolism and diminished therapeutic response in a colorectal cancer model.

Conclusions:

  • p53 acts as a critical regulator of pyrimidine catabolism by repressing DPYD expression, particularly under conditions of metabolic stress.
  • The p53-DPYD axis influences the pharmacokinetics and efficacy of the widely used chemotherapeutic agent 5-FU.
  • Targeting this pathway could offer new strategies to optimize 5-FU treatment and overcome drug resistance in cancer therapy.

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