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Targeting EZH2 reverses thyroid cell dedifferentiation and enhances iodide uptake in anaplastic thyroid cancer

Diego Claro de Mello1, Marcella Maringolo Cristovão1, Guilherme Henrique2,3

  • 1Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo (USP), Brazil.

FEBS Letters
|October 28, 2025
PubMed

Insights

Anaplastic thyroid cancer cells lose thyroid function due to EZH2. Inhibiting EZH2 with EPZ6438 reactivates thyroid differentiation genes and restores iodide uptake, offering new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Anaplastic thyroid carcinoma (ATC) is an aggressive cancer with dedifferentiation and radioiodine resistance.
  • The role of EZH2-mediated epigenetic silencing in ATC dedifferentiation is not fully understood.

Purpose of the Study:

  • To investigate if EZH2-mediated H3K27me3 deposition represses thyroid differentiation genes (TDGs) in ATC.
  • To explore EZH2 inhibition as a therapeutic strategy for ATC.

Main Methods:

  • ChIP-seq and CUT&RUN analyses to identify EZH2/H3K27me3 enrichment at TDGs.
  • Pharmacological inhibition of EZH2 using EPZ6438 in ATC cell lines.
  • Co-treatment with MEK1/2 inhibitor U0126.

Main Results:

  • EZH2 and H3K27me3 were enriched at key TDGs (SLC5A5, NKX2-1, TSHR, FOXE1, TPO) in ATC cells.
  • EPZ6438 treatment reactivated TDG expression and partially restored iodide uptake in ATC cell lines.
  • Combined inhibition of EZH2 and MEK1/2 further enhanced TDG expression.

Conclusions:

  • EZH2 drives ATC dedifferentiation and loss of thyroid-specific functions by repressing TDGs.
  • EZH2 inhibition represents a potential therapeutic approach to restore thyroid function and improve radioiodine sensitivity in ATC.
Keywords:
EZH2NISTazemetostatanaplastic thyroid canceriodide uptakethyroid differentiation

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