Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Oncogene. 2023 Jun;42(23):1900-1912. doi: 10.1038/s41388-023-02695-6. Epub 2023 Apr 25.
Osteosarcoma is the most common bone tumor that leads to high mortality in adolescents and children. The tRNA N-methylguanosine methyltransferase METTL1 is located in chromosome 12q14.1, a region that is frequently amplified in osteosarcoma patients, while its functions and underlying mechanisms in regulation of osteosarcoma remain unknown. Herein we show that METTL1 and WDR4 are overexpressed in osteosarcoma and associated with poor patient prognosis. Knockdown of METTL1 or WDR4 causes decreased tRNA mG modification level and impairs osteosarcoma progression in vitro and in vivo. Conversely, METTL1/WDR4 overexpression promotes osteosarcoma proliferation, migration and invasion capacities. tRNA methylation and mRNA translation profiling indicate that METTL1/WDR4 modified tRNAs enhance translation of mRNAs with more mG tRNA-decoded codons, including extracellular matrix (ECM) remodeling effectors, which facilitates osteosarcoma progression and chemoresistance to doxorubicin. Our study demonstrates METTL1/WDR4 mediated tRNA mG modification plays crucial oncogenic functions to enhance osteosarcoma progression and chemoresistance to doxorubicin via alteration of oncogenic mRNA translation, suggesting METTL1 inhibition combined with chemotherapy is a promising strategy for treatment of osteosarcoma patients.
骨肉瘤是导致青少年和儿童死亡率较高的最常见骨肿瘤。tRNA N-甲基鸟苷甲基转移酶 METTL1 位于染色体 12q14.1 上，该区域在骨肉瘤患者中经常扩增，但其在调节骨肉瘤中的功能和潜在机制尚不清楚。本文表明，METTL1 和 WDR4 在骨肉瘤中过度表达，与患者预后不良相关。METTL1 或 WDR4 的敲低会导致 tRNA mG 修饰水平降低，并在体外和体内损害骨肉瘤的进展。相反，METTL1/WDR4 的过表达促进骨肉瘤的增殖、迁移和侵袭能力。tRNA 甲基化和 mRNA 翻译谱分析表明，METTL1/WDR4 修饰的 tRNA 增强了具有更多 mG tRNA 解码密码子的 mRNA 的翻译，包括细胞外基质（ECM）重塑效应物，这促进了骨肉瘤的进展和对阿霉素的耐药性。我们的研究表明，METTL1/WDR4 介导的 tRNA mG 修饰通过改变致癌 mRNA 的翻译，发挥关键的致癌功能，增强骨肉瘤的进展和对阿霉素的耐药性，提示 METTL1 抑制联合化疗是治疗骨肉瘤患者的一种有前途的策略。
