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MDM2 Antagonist Nutlin-3 Stimulates Global DNA Hydroxymethylation by Enhancing p53-TET1 Signaling Axis

Danni Wu1,2,3, Yao Li1, Cuiping Li1

  • 1State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.

ACS Chemical Biology
|July 18, 2023
PubMed

Insights

The anticancer drug nutlin-3 boosts DNA hydroxymethylation in TP53 wild-type cancer cells by activating p53-TET1 interactions. This process enhances p53 activation, promoting apoptosis through a positive feedback loop.

Area of Science:

  • Epigenetics and Cancer Biology
  • Molecular Oncology
  • DNA Modifications

Background:

  • DNA hydroxymethylation, marked by 5-hydroxymethylcytosine (5hmC), is crucial for cellular processes like development and tumor suppression.
  • The TET family of enzymes (TET1, TET2, TET3) catalyzes the conversion of 5-methylcytosine (5mC) to 5hmC.

Purpose of the Study:

  • To investigate the effect of the anticancer agent nutlin-3 on DNA hydroxymethylation.
  • To elucidate the role of TP53 and TET proteins in nutlin-3-mediated epigenetic changes.

Main Methods:

  • Assessing global DNA hydroxymethylation levels (5hmC) in cancer cells treated with nutlin-3.
  • Analyzing the expression of TET1, TET2, and TET3 proteins.
  • Investigating the interaction between p53 and TET1 using immunoprecipitation.
  • Evaluating the impact of TET1 knockdown on nutlin-3's effects.

Main Results:

  • Nutlin-3 selectively increased global DNA hydroxymethylation in TP53 wild-type cancer cells but not in TP53-mutated cells.
  • Nutlin-3 activated wild-type TP53 but not mutated TP53, consistent with its role as an MDM2 antagonist.
  • TET1 knockdown inhibited nutlin-3-induced DNA hydroxymethylation and TP53/P21 activation.
  • p53 was found to strongly interact with TET1.

Conclusions:

  • Nutlin-3 stimulates DNA hydroxymethylation and apoptosis in a TP53-dependent manner.
  • A positive feedback loop involving p53-TET1 interaction enhances p53 activation and promotes apoptosis.
  • Nutlin-3 represents a potential therapeutic strategy targeting epigenetic modifications in cancer.

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