EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma

Area of Science:

• Molecular Oncology
• Cancer Biology
• Epigenetics

Background:

• Glioblastoma (GBM) is the most prevalent adult malignant brain tumor, with poorly understood molecular drivers.
• The role and expression of YTHDF2 in GBM pathogenesis are largely unknown.
• Epidermal Growth Factor Receptor (EGFR) signaling is frequently dysregulated in GBM.

Purpose of the Study:

• To investigate the role of YTHDF2 in glioblastoma development and progression.
• To elucidate the regulatory mechanisms controlling YTHDF2 expression and function in GBM.
• To explore the impact of YTHDF2 on glioblastoma cell behavior and patient survival.

Main Methods:

• Analysis of YTHDF2 expression in glioma patient data.
• Investigating the EGFR/SRC/ERK pathway's effect on YTHDF2 protein stability.
• Assessing YTHDF2's role in GBM cell proliferation, invasion, and tumorigenesis.
• Studying YTHDF2-mediated regulation of LXRA and HIVEP2 mRNA decay.
• Examining YTHDF2's influence on LXRα-dependent cholesterol homeostasis.

Main Results:

• YTHDF2 overexpression is linked to poorer prognosis in glioma patients.
• EGFR signaling stabilizes YTHDF2 protein via phosphorylation at serine 39 and threonine 381.
• YTHDF2 is essential for GBM cell proliferation, invasion, and tumor formation.
• YTHDF2 promotes tumorigenesis by downregulating LXRA and HIVEP2 mRNA, affecting patient survival.
• YTHDF2 impairs LXRα-mediated cholesterol homeostasis in GBM cells.

Conclusions:

• YTHDF2 is a key mediator of glioblastoma tumorigenesis, regulated by EGFR signaling.
• YTHDF2's function in GBM involves controlling mRNA decay of specific targets and impacting cholesterol metabolism.
• These findings highlight the critical role of RNA m6A methylation in glioblastoma and cholesterol homeostasis.