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RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming

Author

Listed:
  • Huilong Yin

    (Fourth Military Medical University
    Xinxiang Medical University
    Fourth Military Medical University
    Xinxiang Medical University)

  • Xiang Zhang

    (Fourth Military Medical University)

  • Pengyuan Yang

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

  • Xiaofang Zhang

    (Fourth Military Medical University)

  • Yingran Peng

    (Fourth Military Medical University)

  • Da Li

    (Fourth Military Medical University)

  • Yanping Yu

    (The Second Ward of Gynecological Tumor, Shaanxi Provincial Tumor Hospital)

  • Ye Wu

    (Fourth Military Medical University)

  • Yidi Wang

    (Fourth Military Medical University)

  • Jinbao Zhang

    (Fourth Military Medical University)

  • Xiaochen Ding

    (Fourth Military Medical University)

  • Xiangpeng Wang

    (Xinxiang Medical University
    Xinxiang Medical University)

  • Angang Yang

    (Fourth Military Medical University
    Xinxiang Medical University
    Xinxiang Medical University)

  • Rui Zhang

    (Fourth Military Medical University
    Fourth Military Medical University)

Abstract

N6-methyladenosine (m6A) is a reversible mRNA modification that has been shown to play important roles in various biological processes. However, the roles of m6A modification in macrophages are still unknown. Here, we discover that ablation of Mettl3 in myeloid cells promotes tumour growth and metastasis in vivo. In contrast to wild-type mice, Mettl3-deficient mice show increased M1/M2-like tumour-associated macrophage and regulatory T cell infiltration into tumours. m6A sequencing reveals that loss of METTL3 impairs the YTHDF1-mediated translation of SPRED2, which enhances the activation of NF-kB and STAT3 through the ERK pathway, leading to increased tumour growth and metastasis. Furthermore, the therapeutic efficacy of PD-1 checkpoint blockade is attenuated in Mettl3-deficient mice, identifying METTL3 as a potential therapeutic target for tumour immunotherapy.

Suggested Citation

  • Huilong Yin & Xiang Zhang & Pengyuan Yang & Xiaofang Zhang & Yingran Peng & Da Li & Yanping Yu & Ye Wu & Yidi Wang & Jinbao Zhang & Xiaochen Ding & Xiangpeng Wang & Angang Yang & Rui Zhang, 2021. "RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21514-8
    DOI: 10.1038/s41467-021-21514-8
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    Cited by:

    1. Xiang Zhang & Huilong Yin & Xiaofang Zhang & Xunliang Jiang & Yongkang Liu & Haolin Zhang & Yingran Peng & Da Li & Yanping Yu & Jinbao Zhang & Shuli Cheng & Angang Yang & Rui Zhang, 2022. "N6-methyladenosine modification governs liver glycogenesis by stabilizing the glycogen synthase 2 mRNA," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Yinliang Zhang & Chunyuan Du & Wei Wang & Wei Qiao & Yuhui Li & Yujie Zhang & Sufang Sheng & Xuenan Zhou & Lei Zhang & Heng Fan & Ying Yu & Yong Chen & Yunfei Liao & Shihong Chen & Yongsheng Chang, 2024. "Glucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Xiao Han & Lijuan Liu & Saihua Huang & Wenfeng Xiao & Yajing Gao & Weitao Zhou & Caiyan Zhang & Hongmei Zheng & Lan Yang & Xueru Xie & Qiuyan Liang & Zikun Tu & Hongmiao Yu & Jinrong Fu & Libo Wang & , 2023. "RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Cristina Leoni & Marian Bataclan & Taku Ito-Kureha & Vigo Heissmeyer & Silvia Monticelli, 2023. "The mRNA methyltransferase Mettl3 modulates cytokine mRNA stability and limits functional responses in mast cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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