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Epigenetic Remodeling Through GSK343-induced EZH2 Inhibition Alters SMYD2/SMYD3 Expression and Promotes Antitumor

Thaís Amanda Damasceno Silva1, Eduardo Vignoto Fernandes2, Mayara Bocchi2

  • 1Laboratory of Human and Medical Genetics, Federal University of Jataí, Jataí-GO, Brazil.

Clinical Breast Cancer
|August 17, 2026
PubMed
Abstract

Insights

The EZH2 inhibitor GSK343 effectively reduced breast cancer cell viability and increased apoptosis, particularly in triple-negative subtypes. This highlights EZH2 and SMYD family members as promising epigenetic targets for breast cancer therapy.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Breast cancer is a heterogeneous disease driven by epigenetic dysregulation.
  • Enhancer of Zeste Homolog 2 (EZH2) is a key epigenetic regulator involved in H3K27 trimethylation and transcriptional repression, acting as an oncogenic driver.
  • This study investigates the effects of the EZH2 inhibitor GSK343 on breast cancer cells, focusing on its impact on SMYD2 and SMYD3 expression.

Purpose of the Study:

  • To evaluate the anti-tumor effects of the EZH2 inhibitor GSK343 in breast cancer models.
  • To investigate the impact of GSK343 on the expression of epigenetic regulators SMYD2 and SMYD3.
  • To explore subtype-specific vulnerabilities in breast cancer related to EZH2 inhibition.

Main Methods:

  • Human breast cancer cell lines (MDA-MB-231 and MCF-7) were treated with varying concentrations of GSK343.
  • Cell viability was assessed using MTT and Trypan Blue assays.
  • Apoptosis, gene expression (EZH2, SMYD2, SMYD3), and H3K27me3 levels were quantified to assess drug efficacy and mechanism of action.

Main Results:

  • GSK343 significantly reduced cell viability and increased apoptosis in a dose- and time-dependent manner, with greater sensitivity in triple-negative MDA-MB-231 cells.
  • Treatment led to downregulation of EZH2, SMYD2, and SMYD3, with a decrease in H3K27me3 levels, confirming effective epigenetic modulation.
  • These findings indicate that EZH2 inhibition promotes epigenetic remodeling and disrupts oncogenic pathways, revealing subtype-specific dependencies.

Conclusions:

  • EZH2 inhibition demonstrates subtype-specific vulnerabilities in breast cancer, supporting its role as a therapeutic strategy.
  • Targeting epigenetic regulators like EZH2 offers a promising approach for breast cancer treatment, especially for aggressive subtypes.
  • Potential for combinatorial therapies integrating EZH2 inhibition with other treatments to enhance efficacy and overcome resistance in triple-negative breast cancer warrants further investigation.
Keywords:
Breast cancerEZH2 inhibitionEpigenetic regulationGSK343SMYD2/3

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