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N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism

Author

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  • Yanying Wang

    (Chinese Academy of Sciences)

  • Jing Wang

    (Chinese Academy of Sciences)

  • Xiaoyu Li

    (Peking University)

  • Xushen Xiong

    (Peking University)

  • Jianyi Wang

    (Chinese Academy of Sciences)

  • Ziheng Zhou

    (Chinese Academy of Sciences)

  • Xiaoxiao Zhu

    (Chinese Academy of Sciences)

  • Yang Gu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Dan Dominissini

    (Tel Aviv University)

  • Lei He

    (PLA General Hospital)

  • Yong Tian

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Chengqi Yi

    (Peking University)

  • Zusen Fan

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is characterized by high recurrence and heterogeneity, yet its mechanism is not well understood. Here we show that N1-methyladenosine methylation (m1A) in tRNA is remarkably elevated in hepatocellular carcinoma (HCC) patient tumour tissues. Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumours and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylation is required for liver tumourigenesis. Mechanistically, TRMT6/TRMT61A elevates the m1A methylation in a subset of tRNA to increase PPARδ translation, which in turn triggers cholesterol synthesis to activate Hedgehog signaling, eventually driving self-renewal of liver CSCs and tumourigenesis. Finally, we identify a potent inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer.

Suggested Citation

  • Yanying Wang & Jing Wang & Xiaoyu Li & Xushen Xiong & Jianyi Wang & Ziheng Zhou & Xiaoxiao Zhu & Yang Gu & Dan Dominissini & Lei He & Yong Tian & Chengqi Yi & Zusen Fan, 2021. "N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26718-6
    DOI: 10.1038/s41467-021-26718-6
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    1. Hongna Zuo & Aiwei Wu & Mingwei Wang & Liquan Hong & Hu Wang, 2024. "tRNA m1A modification regulate HSC maintenance and self-renewal via mTORC1 signaling," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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