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N7-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis

Author

Listed:
  • Hui Han

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University)

  • Chunlong Yang

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University)

  • Jieyi Ma

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University)

  • Shuishen Zhang

    (The First Affiliated Hospital, Sun Yat-sen University)

  • Siyi Zheng

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University)

  • Rongsong Ling

    (Institute for Advanced Study, Shenzhen University)

  • Kaiyu Sun

    (The First Affiliated Hospital of Sun Yat-sen University)

  • Siyao Guo

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University)

  • Boxuan Huang

    (Institute for Advanced Study, Shenzhen University)

  • Yu Liang

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University)

  • Lu Wang

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University)

  • Shuang Chen

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University)

  • Zhaoyu Wang

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University)

  • Wei Wei

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University)

  • Ying Huang

    (The First Affiliated Hospital, Sun Yat-sen University)

  • Hao Peng

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University)

  • Yi-Zhou Jiang

    (Institute for Advanced Study, Shenzhen University)

  • Junho Choe

    (College of Natural Sciences, Hanyang University
    Research Institute for Natural Sciences, Hanyang University)

  • Shuibin Lin

    (Precision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University
    State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center)

Abstract

Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA m7G methyltransferase complex proteins METTL1 and WDR4 are significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. In addition, METTL1 and WDR4 promote ESCC progression via the tRNA m7G methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of m7G-modified tRNAs and reduces the translation of a subset of oncogenic transcripts enriched in RPTOR/ULK1/autophagy pathway. Furthermore, ESCC models using Mettl1 conditional knockout and knockin mice uncover the essential function of METTL1 in promoting ESCC tumorigenesis in vivo. Our study demonstrates the important oncogenic function of mis-regulated tRNA m7G modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment.

Suggested Citation

  • Hui Han & Chunlong Yang & Jieyi Ma & Shuishen Zhang & Siyi Zheng & Rongsong Ling & Kaiyu Sun & Siyao Guo & Boxuan Huang & Yu Liang & Lu Wang & Shuang Chen & Zhaoyu Wang & Wei Wei & Ying Huang & Hao Pe, 2022. "N7-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29125-7
    DOI: 10.1038/s41467-022-29125-7
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    References listed on IDEAS

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    1. Junho Choe & Shuibin Lin & Wencai Zhang & Qi Liu & Longfei Wang & Julia Ramirez-Moya & Peng Du & Wantae Kim & Shaojun Tang & Piotr Sliz & Pilar Santisteban & Rani E. George & William G. Richards & Kwo, 2018. "mRNA circularization by METTL3–eIF3h enhances translation and promotes oncogenesis," Nature, Nature, vol. 561(7724), pages 556-560, September.
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    Cited by:

    1. Yudong Fu & Fan Jiang & Xiao Zhang & Yingyi Pan & Rui Xu & Xiu Liang & Xiaofen Wu & Xingqiang Li & Kaixuan Lin & Ruona Shi & Xiaofei Zhang & Dominique Ferrandon & Jing Liu & Duanqing Pei & Jie Wang & , 2024. "Perturbation of METTL1-mediated tRNA N7- methylguanosine modification induces senescence and aging," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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