N7-methylguanosine tRNA modification promotes tumorigenesis and chemoresistance through WNT/β-catenin pathway in nasopharyngeal carcinoma
N7-methylguanosine tRNA modification promotes tumorigenesis and chemoresistance through WNT/β-catenin pathway in nasopharyngeal carcinoma
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DOI：
10.1038/s41388-022-02250-9
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发表时间：
2022-02-26
期刊：
影响因子：
8
通讯作者：
Peng, Hao
中科院分区：
文献类型：
--
作者：
Chen, Binbin;Jiang, Wei;Peng, Hao
对于出现疾病进展的晚期鼻咽癌（NPC）患者，治疗选择非常有限。揭示NPC进展的潜在机制对于开发新型治疗方法至关重要。我们发现N-7-甲基鸟苷（m（7）G）tRNA修饰酶胃L1及其伴侣WDR 4在NPC中显著升高，并与不良预后相关。功能丧失和功能获得实验表明，胃L1/WDR 4在体外和体内促进NPC生长和转移。从机制上讲，ARNT被鉴定为调节NPC中胃L1表达的上游转录因子。胃L1缺失导致m（7）G tRNA修饰和表达减少，这导致mRNA翻译过程中密码子识别受损，因此降低了具有较高m（7）G密码子的mRNA的翻译效率。胃L1上调WNT/beta-catenin信号通路，促进鼻咽癌细胞上皮间质转化（EMT）和对顺铂和多西他赛的耐药性。WNT 3A的过表达绕过了胃L1对EMT和化疗耐药性的要求。这项工作揭示了tRNA修饰介导的mRNA翻译调控的新见解，并强调了tRNA修饰在癌症进展中的关键作用。
Treatment selections are very limited for patients with advanced nasopharyngeal carcinoma (NPC) experiencing disease progression. Uncovering mechanisms underlying NPC progression is crucial for the development of novel treatments. Here we show that N-7-methylguanosine (m(7)G) tRNA modification enzyme METTL1 and its partner WDR4 are significantly elevated in NPC and are associated with poor prognosis. Loss-of-function and gain-of-function assays demonstrated that METTL1/WDR4 promotes NPC growth and metastasis in vitro and in vivo. Mechanistically, ARNT was identified as an upstream transcription factor regulating METTL1 expression in NPC. METTL1 depletion resulted in decreased m(7)G tRNA modification and expression, which led to impaired codon recognition during mRNA translation, therefore reducing the translation efficiencies of mRNAs with higher m(7)G codons. METTL1 upregulated the WNT/beta-catenin signaling pathway and promoted NPC cell epithelial-mesenchymal transition (EMT) and chemoresistance to cisplatin and docetaxel in vitro and in vivo. Overexpression of WNT3A bypassed the requirement of METTL1 for EMT and chemoresistance. This work uncovers novel insights into tRNA modification-mediated mRNA translation regulation and highlights the critical function of tRNA modification in cancer progression.