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EZH2 Exacerbates Breast Cancer by Methylating and Activating STAT3 Directly

Yi Zhao1, Zhansheng Hu1, Jincheng Li1

  • 1The First Affiliated Hospital of Jinzhou Medical University.

Journal of Cancer
|August 2, 2021
PubMed

Insights

Enhancer of zeste homolog 2 (EZH2) drives breast cancer by directly methylating STAT3, impacting its function and promoting tumor growth. Targeting this non-canonical EZH2-STAT3 interaction offers a new therapeutic strategy for breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Breast cancer remains a leading global cause of female mortality.
  • Existing treatments face challenges with side effects and drug resistance.
  • The non-canonical functions of Enhancer of zeste homolog 2 (EZH2) in breast cancer are not well understood.

Purpose of the Study:

  • To investigate the non-canonical role of EZH2 in breast cancer progression.
  • To elucidate the mechanism by which EZH2 influences breast cancer development.
  • To identify EZH2 as a potential therapeutic target.

Main Methods:

  • Analysis of TCGA datasets to assess EZH2 and STAT3 expression.
  • In vitro experiments using chemical and genetic inhibition of EZH2 in breast cancer cells.
  • Co-immunoprecipitation and methylation assays to study EZH2-STAT3 interaction.
  • In vivo studies in animal models of breast cancer.

Main Results:

  • EZH2 is over-expressed in breast cancer patients and regulates STAT3 post-transcriptionally.
  • EZH2 directly interacts with and methylates STAT3, increasing its nuclear localization and chromatin binding.
  • Inhibition of EZH2 reduces breast cancer cell proliferation and migration, partially rescued by STAT3 overexpression.
  • Targeting the STAT3 methylation site impeded its transcriptional activity.
  • Disrupting STAT3 methylation by EZH2 in vivo decreased tumor growth.

Conclusions:

  • EZH2 exacerbates breast cancer through the non-canonical methylation of STAT3.
  • This EZH2-mediated STAT3 methylation promotes breast cancer growth and progression.
  • The EZH2-STAT3 pathway represents a promising therapeutic target for breast cancer treatment.
Keywords:
Breast cancerEZH2MethylationSTAT3

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