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Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage

Annarita Nappi1, Caterina Miro1, Antonio Pezone2

  • 1Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131, Naples, Italy.

Nature Communications
|March 4, 2023
PubMed

Insights

The tumor suppressor p53 normally silences the thyroid hormone (TH) activating enzyme, type 2 deiodinase (D2). Loss of p53 increases D2 and TH, promoting cancer cell growth and fitness.

Area of Science:

  • Oncology
  • Endocrinology
  • Molecular Biology

Background:

  • Type 2 deiodinase (D2) activates thyroid hormone (TH) and is crucial for cancer progression.
  • Mechanisms regulating D2 in cancer are not well understood.

Purpose of the Study:

  • To investigate the role of p53 in regulating D2 expression in cancer.
  • To understand how p53-mediated D2 regulation impacts tumor cell behavior.

Main Methods:

  • Utilized cell culture and in vivo models to study p53 and D2 interactions.
  • Analyzed gene expression and tumor progression in response to p53 and D2 modulation.

Main Results:

  • The tumor suppressor p53 directly silences D2 expression, reducing intracellular TH availability.
  • Loss of p53 function leads to elevated D2 and TH levels, enhancing tumor cell fitness.
  • Elevated TH promotes a transcriptional program involving DNA repair and redox signaling.
  • In vivo deletion of D2 significantly inhibited cancer progression in p53-mutated models.

Conclusions:

  • p53 acts as a negative regulator of D2 in cancer.
  • Targeting TH signaling may be a therapeutic strategy for p53-mutated cancers.
  • D2-mediated TH signaling supports tumor cell adaptation and progression.

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