journal contribution
posted on 2023-03-31, 06:02 authored by Manling Huang, Jianting Long, Zhijia Yao, Yi Zhao, Yutong Zhao, Junbin Liao, Kai Lei, Han Xiao, Zihao Dai, Sui Peng, Shuibin Lin, Lixia Xu, Ming Kuang This file shows the antibodies used in the study.
Funding
National Natural Science Foundation of China (NSFC)
Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)
Basic and Applied Basic Research Foundation of Guangdong Province (廣東省基礎與應用基礎研究專項資金)
National Postdoctoral Program for Innovative Talents (Postdoctoral Innovation Talent Support Program of China)
China Postdoctoral Science Foundation
History
ARTICLE 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 methyltransferase-like protein-1 (METTL1) and WD repeat domain 4 protein (WDR4), the two key components of the tRNA N7-methylguanosine (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.
Upregulation of tRNA m7G methyltransferase complex components METTL1 and WDR4 promotes lenvatinib resistance in HCC and confers a sensitivity to METTL1 targeting, providing a promising strategy to override resistance.
