METTL3 Promotes OSCC Progression by Down-Regulating WEE1 in a m6A-YTHDF2-Dependent Manner

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Oral squamous cell carcinoma (OSCC) is a significant cause of cancer-related deaths.
• The role of RNA methylation in OSCC progression requires further elucidation.
• METTL3 is implicated in various cancers, but its specific mechanisms in OSCC are not fully understood.

Purpose of the Study:

• To confirm the role of METTL3 in promoting OSCC.
• To investigate the underlying molecular mechanisms of METTL3 in OSCC.
• To explore the relationship between METTL3, YTHDF2, and WEE1 in OSCC.

Main Methods:

• Expression analysis of METTL3, YTHDF2, and WEE1 in OSCC cells and tissues.
• Functional assays (proliferation, invasion, migration, apoptosis) after WEE1 overexpression.
• MeRIP-qPCR to detect WEE1 m6A levels.
• Knockdown experiments for METTL3/YTHDF2 to assess WEE1 levels and mRNA stability.
• In vivo studies using a nude mouse model of OSCC.
• Immunohistochemistry for Ki-67 and WEE1 expression.

Main Results:

• METTL3 and YTHDF2 were upregulated, while WEE1 was downregulated in OSCC cells.
• WEE1 overexpression inhibited OSCC cell proliferation, invasion, and migration, and promoted apoptosis.
• METTL3 and YTHDF2 bind to WEE1 mRNA, leading to its downregulation and reduced stability.
• METTL3 inhibition decreased WEE1 m6A levels and weakened YTHDF2-WEE1 interaction.
• In vivo, WEE1 overexpression suppressed OSCC development, an effect reversed by YTHDF2 overexpression.

Conclusions:

• METTL3 promotes OSCC progression via the m6A-YTHDF2 pathway, which downregulates WEE1.
• WEE1 acts as a tumor suppressor in OSCC.
• Targeting the METTL3/YTHDF2/WEE1 axis may offer a novel therapeutic strategy for OSCC.