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METTL1/WDR4-mediated tRNA m7G modification and mRNA translation control promote oncogenesis and doxorubicin resistance

Oncogene volume 42, pages 1900–1912 (2023)Cite this article

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Abstract

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.

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Fig. 1: METTL1 and WDR4 are elevated in osteosarcoma and correlated with poor prognosis.
Fig. 2: METTL1 knockdown inhibits osteosarcoma malignancy.
Fig. 3: WDR4 depletion recapitulates METTL1 mediated cell functional changes and METTL1 depletion hinders tumor growth in vivo.
Fig. 4: METTL1/WDR4 overexpression enhances proliferation, migration and invasion of osteosarcoma cell lines.
Fig. 5: METTL1 depletion causes reduced m7G modification, m7G-modified tRNAs and altered global mRNA translation.
Fig. 6: Overexpression of LOXL2 rescues proliferation, migration and invasion of METTL1/WDR4-depleted HOS cells.
Fig. 7: METTL1 depletion promotes osteosarcoma vulnerability to doxorubicin in vitro and in vivo.

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Acknowledgements

This research was supported by grants from National Key Research and Development Plan (2022YFA1105300, 2022YFE0138700), National Natural Science Foundation of China (81974435, 81922052), Natural Science Foundation of Guangdong Province (2019B151502011), Natural Science Foundation of Guangdong (2021A1515111032) and National Natural Science Foundation of China (82200954).

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Author notes

  1. These authors contributed equally: Zhaoyu Wang, Peng Yu, Yutong Zou.

Authors and Affiliations

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

    Zhaoyu Wang, Jieyi Ma, Hui Han, Wei Wei, Chunlong Yang, Siyi Zheng, Siyao Guo & Shuibin Lin

  2. The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Peng Yu

  3. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong, China

    Peng Yu

  4. Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China

    Yutong Zou

  5. Laboratory of General Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China

    Jieyi Ma

  6. Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China

    Juan Wang

  7. Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China

    Lianlian Liu

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Contributions

ZW, PY, YZ designed experiments, acquired, analyzed and interpreted data and wrote the manuscript; JM, HH, WW, CY, SZ, SG, JW, and LL helped with some experiments and data interpretation; SL designed, supervised the study, and wrote manuscript.

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Correspondence to Shuibin Lin.

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Wang, Z., Yu, P., Zou, Y. et al. METTL1/WDR4-mediated tRNA m7G modification and mRNA translation control promote oncogenesis and doxorubicin resistance. Oncogene 42, 1900–1912 (2023). https://doi.org/10.1038/s41388-023-02695-6

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