G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Breast cancer is heterogeneous, with claudin-low breast cancer (CLBC) subtypes exhibiting early metastasis and chemoresistance.
• Epithelial-mesenchymal transition (EMT) markers are characteristic of CLBC, and decreased E-cadherin expression, a hallmark of EMT, is linked to poor patient survival.

Purpose of the Study:

• To elucidate the epigenetic mechanisms regulating E-cadherin expression in CLBC.
• To investigate the role of histone methylation in the DNA methylation of the E-cadherin promoter.
• To explore therapeutic strategies targeting epigenetic regulators for CLBC treatment.

Main Methods:

• Utilized TGF-β-induced EMT cell lines and CLBC cell lines.
• Investigated the role of histone H3 lysine 9 dimethylation (H3K9me2) in E-cadherin promoter methylation.
• Examined the interaction between Snail, G9a (euchromatin methyltransferase), and DNA methyltransferases.
• Performed G9a knockdown experiments.
• Assessed cell migration, invasion, tumor growth, and lung colonization in vitro and in vivo models.

Main Results:

• H3K9me2 is critical for E-cadherin promoter DNA methylation in EMT and CLBC models.
• Snail recruits G9a and DNA methyltransferases to the E-cadherin promoter.
• G9a knockdown reversed E-cadherin suppression, inhibited H3K9me2 and DNA methylation, and reduced CLBC cell migration, invasion, tumor growth, and metastasis.
• Restored E-cadherin expression via G9a inhibition suppressed tumor growth and lung colonization.

Conclusions:

• Identified a novel epigenetic regulatory pathway involving H3K9me2 and G9a in controlling E-cadherin expression during EMT.
• Demonstrated that targeting G9a can reverse epigenetic silencing of E-cadherin, offering a potential therapeutic strategy for CLBC.