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Activation of EZH2 Promoter Is Mediated by MAPK Signaling Regulated Transcription Factors in Anaplastic Thyroid

Marcella Maringolo Cristovão1, Diego Claro de Mello1, Edna Teruko Kimura1

  • 1Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo 05508-000, SP, Brazil.

International Journal of Molecular Sciences
|July 28, 2026
PubMed

Insights

Anaplastic thyroid carcinoma (ATC) involves EZH2 overexpression, driving aggressive cancer. This study identifies a minimal promoter region for EZH2 activation, regulated by MAPK signaling and key transcription factors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid cancer subtype.
  • EZH2 overexpression in ATC contributes to tumor progression by silencing tumor suppressor genes.
  • Understanding EZH2 transcriptional regulation is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the transcriptional activation mechanism of EZH2 in ATC.
  • To identify the minimal promoter region responsible for EZH2 activation.
  • To explore the crosstalk between MAPK signaling, transcription factors (TFs), and EZH2 expression.

Main Methods:

  • Utilized luciferase reporter constructs with deleted TF binding sites to define the EZH2 minimal promoter.
  • Employed MAPK signaling inhibition (U0126), TF overexpression, and knockdown strategies.
  • Analyzed EZH2 expression, reporter plasmid activity, and TF interactions.

Main Results:

  • Identified a 107 bp minimal promoter region (E3/4) essential for EZH2 activation in ATC.
  • This region contains binding sites for NFYA, YY1, and FOXM1, which are highly expressed in ATC.
  • MAPK inhibition decreased EZH2 levels and affected YY1 and FOXM1 expression.
  • Overexpression of NFYA, YY1, and FOXM1 upregulated EZH2 and promoted tumor effects in papillary thyroid cancer cells.
  • FOXM1 knockdown reduced EZH2 activation in ATC cells.

Conclusions:

  • EZH2 transcription in ATC is regulated by a specific minimal promoter (E3/4 region).
  • MAPK signaling pathways crosstalk with TFs NFYA, YY1, and FOXM1 to control EZH2 activation.
  • These findings elucidate a key regulatory mechanism of EZH2 in aggressive thyroid cancer.
Keywords:
EZH2MAPK signalinganaplastic thyroid cancerpromoter regiontranscription factorstranscriptional control

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