METTL1/WDR4-mediated tRNA m7G modification and mRNA translation control promote oncogenesis and doxorubicin resistance
METTL1/WDR4-mediated tRNA m7G modification and mRNA translation control promote oncogenesis and doxorubicin resistance
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DOI：
10.1038/s41388-023-02695-6
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发表时间：
2023-04
期刊：
影响因子：
8
通讯作者：
Zhaoyu Wang;Peng Yu;Yutong Zou;Jieyi Ma;Hui Han;Wei Wei-Wei;Chunlong Yang;Siyi Zheng;Siyao Guo;Juanjing Wang;Lianlian Liu;Shuibin Lin
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文献类型：
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作者：
Zhaoyu Wang;Peng Yu;Yutong Zou;Jieyi Ma;Hui Han;Wei Wei-Wei;Chunlong Yang;Siyi Zheng;Siyao Guo;Juanjing Wang;Lianlian Liu;Shuibin Lin
骨肉瘤是最常见的骨肿瘤，导致青少年和儿童的高死亡率。tRNA N7-甲基鸟苷甲基转移酶胃L1位于染色体12q14.1，该区域在骨肉瘤患者中经常扩增，但其在骨肉瘤调节中的功能和潜在机制尚不清楚。在此，我们发现骨肉瘤中胃L1和WDR4过表达，并与患者预后不良相关。在体外和体内，敲除胃L1或WDR4导致tRNA m7G修饰水平降低，并损害骨肉瘤的进展。相反，胃L1/WDR4过表达促进骨肉瘤的增殖、迁移和侵袭能力。tRNA甲基化和mRNA翻译谱表明，胃L1/WDR4修饰的tRNA增强了具有更多m7G 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多柔比星的化疗耐药性。我们的研究表明，胃L1/WDR4介导的tRNA m7G修饰通过改变致癌mRNA的翻译，在增强骨肉瘤进展和对阿霉素的化疗耐药性方面发挥关键的致癌功能，这表明胃L1抑制联合化疗是治疗骨肉瘤患者的有希望的策略。
Osteosarcoma is the most common bone tumor that leads to high mortality in adolescents and children. The tRNA N7-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 m7G 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 m7G tRNA-decoded codons, including extracellular matrix (ECM) remodeling effectors, which facilitates osteosarcoma progression and chemoresistance to doxorubicin. Our study demonstrates METTL1/WDR4 mediated tRNA m7G 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.