O-GlcNAcylation of YTHDF2 antagonizes ERK-dependent phosphorylation and inhibits lung carcinoma

Area of Science:

• Molecular Biology
• Cellular Signaling
• Cancer Research

Background:

• Intracellular O-linked N-acetylglucosamine (O-GlcNAc) glycosylation is crucial for signal transduction and tumorigenesis.
• YTHDF2, an m6A reader, is implicated in HBV-related hepatocellular carcinoma via Ser-263 O-GlcNAcylation.

Purpose of the Study:

• To map YTHDF2 O-GlcNAcylation sites under normal conditions.
• To investigate the functional consequences of YTHDF2 O-GlcNAcylation at Thr-49 on tumorigenesis, specifically in lung carcinoma.

Main Methods:

• Electron-transfer dissociation mass spectrometry to map O-GlcNAcylation sites.
• Western blotting and immunoprecipitation to study protein modifications and interactions.
• Mouse xenograft models to assess tumor growth in vivo.

Main Results:

• YTHDF2 O-GlcNAcylation was mapped to Thr-49 under unperturbed conditions.
• Thr-49 O-GlcNAcylation antagonizes ERK phosphorylation at Ser-39, leading to YTHDF2 degradation.
• YTHDF2 degradation upregulates its downstream signaling in lung cancer, downregulating c-Myc.
• YTHDF2-T49A mutants accelerated lung cancer growth in mouse models.

Conclusions:

• YTHDF2 O-GlcNAcylation at Thr-49 plays a critical role in regulating YTHDF2 stability and function.
• This post-translational modification influences lung tumorigenesis by modulating the YTHDF2/c-Myc axis.
• O-GlcNAcylation exhibits distinct roles in tumorigenesis depending on cellular context and stress conditions.