EZH2 Inhibition to Counteract Oral Cancer Progression through Wnt/β-Catenin Pathway Modulation

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with incompletely understood pathogenesis.
• Emerging research highlights the role of enhancer of zeste homolog 2 (EZH2) in OSCC development.
• Targeting EZH2 presents a potential therapeutic strategy for OSCC.

Purpose of the Study:

• To investigate the therapeutic effects of GSK343, a selective EZH2 inhibitor, on OSCC.
• To elucidate the impact of GSK343 on key signaling pathways involved in OSCC progression.
• To evaluate GSK343's efficacy in both in vitro and in vivo orthotopic OSCC models.

Main Methods:

• Utilized in vitro and in vivo orthotopic models of OSCC.
• Administered GSK343 at various concentrations (1, 10, 25 μM in vitro; 5, 10 mg/kg in vivo).
• Assessed cell viability, migration, tumor progression, tissue architecture, and expression of specific molecular markers (e.g., EZH2, NF-κB/IκBα, eNOS, VEGF, TGFβ, Wnt/β-catenin, CD31, CD34).

Main Results:

• GSK343 significantly decreased OSCC cell viability and migration in vitro via EZH2 inhibition.
• In vivo, GSK343 restored tongue tissue architecture and reduced tumor progression.
• GSK343 modulated NF-κB/IκBα, Wnt/β-catenin signaling, and reduced angiogenesis markers (eNOS, VEGF, TGFβ) and microvessel density (CD31, CD34).

Conclusions:

• GSK343 effectively inhibits OSCC progression by targeting EZH2 and modulating critical signaling pathways.
• The study suggests GSK343 as a promising therapeutic agent for managing OSCC.
• Targeting the EZH2/Wnt/β-catenin pathway offers a novel strategy for OSCC treatment.