5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs

Xin Chen, Ang Li, Bao Fa Sun, Ying Yang, Ya Nan Han, Xun Yuan, Ri Xin Chen, Wen Su Wei, Yanchao Liu, Chun Chun Gao, Yu Sheng Chen, Mengmeng Zhang, Xiao Dan Ma, Zhuo Wei Liu, Jun Hang Luo, Cong Lyu, Hai Lin Wang, Jinbiao Ma, Yong Liang Zhao, Fang Jian ZhouYing Huang, Dan Xie, Yun Gui Yang

    Research output: Contribution to journalArticle

    38 Scopus citations

    Abstract

    Although 5-methylcytosine (m5C) is a widespread modification in RNAs, its regulation and biological role in pathological conditions (such as cancer) remain unknown. Here, we provide the single-nucleotide resolution landscape of messenger RNA m5C modifications in human urothelial carcinoma of the bladder (UCB). We identify numerous oncogene RNAs with hypermethylated m5C sites causally linked to their upregulation in UCBs and further demonstrate YBX1 as an m5C ‘reader’ recognizing m5C-modified mRNAs through the indole ring of W65 in its cold-shock domain. YBX1 maintains the stability of its target mRNA by recruiting ELAVL1. Moreover, NSUN2 and YBX1 are demonstrated to drive UCB pathogenesis by targeting the m5C methylation site in the HDGF 3′ untranslated region. Clinically, a high coexpression of NUSN2, YBX1 and HDGF predicts the poorest survival. Our findings reveal an unprecedented mechanism of RNA m5C-regulated oncogene activation, providing a potential therapeutic strategy for UCB.

    Original languageEnglish (US)
    Pages (from-to)978-990
    Number of pages13
    JournalNature cell biology
    Volume21
    Issue number8
    DOIs
    StatePublished - Aug 1 2019

    ASJC Scopus subject areas

    • Cell Biology

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  • Cite this

    Chen, X., Li, A., Sun, B. F., Yang, Y., Han, Y. N., Yuan, X., Chen, R. X., Wei, W. S., Liu, Y., Gao, C. C., Chen, Y. S., Zhang, M., Ma, X. D., Liu, Z. W., Luo, J. H., Lyu, C., Wang, H. L., Ma, J., Zhao, Y. L., ... Yang, Y. G. (2019). 5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs. Nature cell biology, 21(8), 978-990. https://doi.org/10.1038/s41556-019-0361-y