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

Abstract

The tyrosine kinase inhibitor lenvatinib is a first-line drug for treating patients with advanced hepatocellular carcinoma (HCC). However, its efficacy is severely hampered by drug resistance. Insights into the molecular mechanisms underlying lenvatinib resistance could provide new strategies to improve and prolong responses. Here, we performed unbiased proteomic screening of parental and lenvatinib-resistant HCC cells and discovered that METTL1 and WDR4, the two key components of the tRNA m7G methyltransferase complex, were dramatically upregulated in lenvatinib-resistant cells. METTL1 knockdown overrode resistance by impairing the proliferation capacity of HCC cells and promoting apoptosis under lenvatinib treatment. In addition, overexpression of wild-type METTL1 but not its catalytic dead mutant induced lenvatinib resistance. Animal experiments including hydrodynamic injection, subcutaneous implantation, and orthotopic xenograft mouse models further demonstrated the critical function of METTL1/WDR4-mediated m7G tRNA modification in promoting lenvatinib resistance in vivo. Mechanistically, METTL1 promoted translation of EGFR pathway genes to trigger drug resistance. This work reveals the important role of METTL1-mediated m7G tRNA modification in promoting lenvatinib resistance and provides a promising prediction marker and intervention target for resistance.

tRNA Modifications and Modifying Enzymes in Disease, the Potential Therapeutic Targets

“…This research elucidates that the METTL1-m 7 G-SLUG/SNAIL axis has the potential to be a therapeutic target for preventing metastasis of HCC after radiofrequency thermal ablation [90]. In addition, a recent study demonstrated that m 7 G tRNA modification is critical for enhancing lenvatinib resistance in vivo [91], and METTL1 is implicated in 5-FU sensitivity in HeLa cells [92]. These studies suggest that m 7 G modification is associated with drug resistance of tumor cells, and provide a promising diagnostic marker and therapeutic target for drug resistance.…”

Association of RNA m7G Modification Gene Polymorphisms with Pediatric Glioma Risk

“…An unbiased proteomic screening of differentially expressed genes between parental and lenvatinibresistant HCC cells unveiled that METTL1 and WDR4 were highly elevated in drug-resistant cells. METTL1/WDR4-catalyzed m7G tRNA modification led to drug resistance by BioMed Research International [39]. In ICC, METTL1 and WDR4 enhanced the translation of cell-cycle and epidermal growth factor receptor (EGFR) pathway genes in an m 7 G-tRNA-dependent manner.…”

“…METTL1/WDR4-catalyzed m7G tRNA modification led to drug resistance by facilitating the translation of EGFR pathway genes. METTL1 depletion overcame resistance by inhibiting proliferation and inducing apoptosis of HCC cells [ 39 ]. In ICC, METTL1 and WDR4 enhanced the translation of cell-cycle and epidermal growth factor receptor (EGFR) pathway genes in an m 7 G-tRNA-dependent manner.…”

Constructing and validating of m7G-related genes prognostic signature for hepatocellular carcinoma and immune infiltration: potential biomarkers for predicting the overall survival

“…These factors also have an impact on immune cell infiltration in LIHC. Therefore, exploring how m7G influences the onset, development of LIHC is of great importance for future effective target prediction and drug design ( 33 ). In this study, we constructed that a predictive model according to five m7G-related genes ( EIF4E, GEMIN5, NCBP1, NCBP2, WDR4 ) could predict the survival of patients.…”