Mettl1-KO Mouse

METTL1, short for methyltransferase-like protein-1, is a key component of the tRNA N7-methylguanosine (m7G) methyltransferase complex along with WDR4. It catalyzes the m7G modification of tRNAs, which is crucial for tRNA stability and function, and is involved in various biological processes such as translation [4,5,7].

In cancer research, METTL1 has been found to play oncogenic roles. Depletion of METTL1 in cancer cells leads to decreased abundance of m7G-modified tRNAs, altered cell cycle, and inhibited oncogenicity. For instance, in hepatocellular carcinoma, knockdown of METTL1 overrode lenvatinib resistance by impairing cell proliferation and promoting apoptosis [1]. In bladder cancer, silencing METTL1 suppressed cell proliferation, migration, and invasion both in vitro and in vivo [2]. In prostate cancer, knockdown of Mettl1 in pre-clinical models increased intratumoural infiltration of pro-inflammatory immune cells and enhanced responses to immunotherapy [6]. Also, in post-radiofrequency ablation recurrent hepatocellular carcinoma, METTL1 expression was enhanced, accompanied by increased PMN-MDSCs and decreased CD8+ T cells, and interrupting the METTL1-TGF-β2-PMN-MDSC axis could prevent recurrence [3].

In conclusion, METTL1-mediated m7G tRNA modification is essential for normal biological functions, and its dysregulation is closely associated with cancer development and drug resistance. The use of gene knockout or knockdown models in these studies has revealed METTL1's critical role in promoting tumorigenesis, immunosuppressive microenvironment formation, and drug resistance in various cancers, providing potential therapeutic targets for cancer treatment.

References:

1. Huang, Manling, Long, Jianting, Yao, Zhijia, Xu, Lixia, Kuang, Ming. . METTL1-Mediated m7G tRNA Modification Promotes Lenvatinib Resistance in Hepatocellular Carcinoma. In Cancer research, 83, 89-102. doi:10.1158/0008-5472.CAN-22-0963. https://pubmed.ncbi.nlm.nih.gov/36102722/

2. Ying, Xiaoling, Liu, Bixia, Yuan, Zusen, Luo, Junhang, Ji, Weidong. . METTL1-m7 G-EGFR/EFEMP1 axis promotes the bladder cancer development. In Clinical and translational medicine, 11, e675. doi:10.1002/ctm2.675. https://pubmed.ncbi.nlm.nih.gov/34936728/

3. Zeng, Xuezhen, Liao, Guanrui, Li, Shumin, Chen, Shuling, Kuang, Ming. 2022. Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation. In Hepatology (Baltimore, Md.), 77, 1122-1138. doi:10.1002/hep.32585. https://pubmed.ncbi.nlm.nih.gov/35598182/

4. Ruiz-Arroyo, Victor M, Raj, Rishi, Babu, Kesavan, Roberts, Paul H, Nam, Yunsun. 2023. Structures and mechanisms of tRNA methylation by METTL1-WDR4. In Nature, 613, 383-390. doi:10.1038/s41586-022-05565-5. https://pubmed.ncbi.nlm.nih.gov/36599982/

5. Cheng, Wenli, Gao, Aili, Lin, Hui, Zhang, Wenjuan. 2022. Novel roles of METTL1/WDR4 in tumor via m7G methylation. In Molecular therapy oncolytics, 26, 27-34. doi:10.1016/j.omto.2022.05.009. https://pubmed.ncbi.nlm.nih.gov/35784404/

6. García-Vílchez, Raquel, Añazco-Guenkova, Ana M, Dietmann, Sabine, Carracedo, Arkaitz, Blanco, Sandra. 2023. METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer. In Molecular cancer, 22, 119. doi:10.1186/s12943-023-01809-8. https://pubmed.ncbi.nlm.nih.gov/37516825/

7. Li, Jiazhi, Wang, Longfei, Hahn, Quentin, Fischer, Eric S, Gregory, Richard I. 2023. Structural basis of regulated m7G tRNA modification by METTL1-WDR4. In Nature, 613, 391-397. doi:10.1038/s41586-022-05566-4. https://pubmed.ncbi.nlm.nih.gov/36599985/