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

Manling Huang1,2, Jianting Long1, Zhijia Yao1

  • 1Department of Oncology, Cancer Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P.R. China.

Cancer Research
|September 14, 2022
PubMed

Insights

Methyltransferase-like protein-1 (METTL1) and WDR4 upregulation drives lenvatinib resistance in hepatocellular carcinoma (HCC). Targeting METTL1 can overcome this resistance, offering new therapeutic strategies for HCC patients.

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.

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