METTL1-Mediated m7G tRNA Modification Promotes Lenvatinib Resistance in Hepatocellular Carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Lenvatinib is a first-line treatment for advanced hepatocellular carcinoma (HCC).
• Drug resistance significantly limits lenvatinib's efficacy in HCC patients.
• Understanding resistance mechanisms is crucial for improving treatment outcomes.

Purpose of the Study:

• To investigate the molecular mechanisms underlying lenvatinib resistance in HCC.
• To identify potential therapeutic targets for overcoming lenvatinib resistance.

Main Methods:

• Unbiased proteomic screening of parental and lenvatinib-resistant HCC cells.
• Gene knockdown and overexpression studies of METTL1 and WDR4.
• In vivo validation using hydrodynamic injection, subcutaneous implantation, and orthotopic xenograft mouse models.
• Analysis of EGFR pathway gene translation.

Main Results:

• METTL1 and WDR4, key components of the tRNA m7G methyltransferase complex, were significantly upregulated in lenvatinib-resistant HCC cells.
• METTL1 knockdown reversed lenvatinib resistance by inhibiting proliferation and promoting apoptosis.
• METTL1 overexpression induced lenvatinib resistance, while a catalytic dead mutant did not.
• METTL1/WDR4-mediated m7G tRNA modification was critical for lenvatinib resistance in vivo.
• METTL1 promoted EGFR pathway gene translation, contributing to drug resistance.

Conclusions:

• METTL1-mediated m7G tRNA modification plays a critical role in promoting lenvatinib resistance in HCC.
• METTL1 and WDR4 are potential biomarkers for predicting lenvatinib resistance.
• Targeting METTL1 offers a promising strategy to overcome lenvatinib resistance in HCC.