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N7-methylguanosine tRNA modification promotes tumorigenesis and chemoresistance through WNT/β-catenin pathway in nasopharyngeal carcinoma

Oncogene volume 41, pages 2239–2253 (2022)Cite this article

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Abstract

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 N7-methylguanosine (m7G) 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 m7G tRNA modification and expression, which led to impaired codon recognition during mRNA translation, therefore reducing the translation efficiencies of mRNAs with higher m7G codons. METTL1 upregulated the WNT/β-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.

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Fig. 1: METTL1 is upregulated in NPC and associated with poor prognosis.
Fig. 2: Knockdown of METTL1 inhibit tumorigenesis in vitro and in vivo.
Fig. 3: METTL1 promotes NPC progression through its catalytic activity.
Fig. 4: ARNT regulates METTL1 expression.
Fig. 5: METTL1 regulates m7G tRNA methylome and global mRNA translation through codon recognition.
Fig. 6: Overexpressing WNT3A in METTL1 knockout cells promoted NPC progression.
Fig. 7: METTL1 promotes NPC cells EMT.
Fig. 8: METTL1 promotes chemoresistance of NPC cells to cisplatin and docetaxel in vitro and in vivo.

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Data and code availability

The previously published Microarray data that were re-analyzed here are available under the accession code GEO12452 and GEO103611. The chemicals and commercial kits used in this study were shown in Table S7. The polyribosome-RNA-seq, Ribo-seq and m7G tRNA TRAC-seq data generated in this study are available at NCBI GEO DataSet (GSE169589). Software and algorithms employed in this study were presented in Supplementary Table S8.

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Acknowledgements

We sincerely thank professor Jun Ma (Department of Radiation Oncology, Sun Yat-sen University Cancer Center) for kindly donate the NPC cell lines and nasopharyngeal normal cell lines. We sincerely thank Drs. Weidong Ji and Shuibin Lin for kindly sharing us with the plasmids for METTL1 overexpression and depletion. We thank all the patients who generously donate the tissues. The work was funded by National Natural Science Foundation of China (82002981, 82003232 and 82003212) and China Postdoctoral Science Foundation (2020M673003).

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  1. These authors contributed equally: Binbin Chen, Wei Jiang, Ying Huang.

Authors and Affiliations

  1. Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China

    Binbin Chen & Hao Peng

  2. Department of Clinical Nutrition, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China

    Binbin Chen

  3. Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, 541001, China

    Wei Jiang

  4. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China

    Ying Huang

  5. Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, Guangzhou, 510095, P. R. China

    Jian Zhang & Peng Yu

  6. Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China

    Lirong Wu

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Contributions

BC and HP designed the protocol of this study. BC, JZ, PY and HP performed in vitro and in vivo assays. WJ and YH were responsible for the clinical sample tissues. BC performed TRAC-seq and data was analyzed by H.P. Polysome associated mRNA-seq and data analysis were performed by HP and PY. All other data analysis was performed by LW, HP and PY. BC and HP wrote the paper and all authors revised and modified the final paper.

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Correspondence to Lirong Wu or Hao Peng.

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Chen, B., Jiang, W., Huang, Y. et al. N7-methylguanosine tRNA modification promotes tumorigenesis and chemoresistance through WNT/β-catenin pathway in nasopharyngeal carcinoma. Oncogene 41, 2239–2253 (2022). https://doi.org/10.1038/s41388-022-02250-9

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