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Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation

Author

Listed:
  • An Xu

    (The University of Texas Health Science Center at Houston)

  • Mo Liu

    (The University of Texas Health Science Center at Houston)

  • Mo-Fan Huang

    (The University of Texas Health Science Center at Houston
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences)

  • Yang Zhang

    (Harbin Institute of Technology (Shenzhen))

  • Ruifeng Hu

    (The University of Texas Health Science Center at Houston)

  • Julian A. Gingold

    (Einstein/Montefiore Medical Center)

  • Ying Liu

    (The University of Texas Health Science Center at Houston)

  • Dandan Zhu

    (The University of Texas Health Science Center at Houston)

  • Chian-Shiu Chien

    (Taipei Veterans General Hospital
    National Yang Ming Chiao Tung University)

  • Wei-Chen Wang

    (National Chung Hsing University)

  • Zian Liao

    (Baylor College of Medicine)

  • Fei Yuan

    (Baylor College of Medicine)

  • Chih-Wei Hsu

    (Baylor College of Medicine)

  • Jian Tu

    (The University of Texas Health Science Center at Houston)

  • Yao Yu

    (The University of Texas MD Anderson Cancer Center)

  • Taylor Rosen

    (The University of Texas Health Science Center at Houston)

  • Feng Xiong

    (The University of Texas Health Science Center at Houston)

  • Peilin Jia

    (The University of Texas Health Science Center at Houston)

  • Yi-Ping Yang

    (Taipei Veterans General Hospital
    National Yang Ming Chiao Tung University)

  • Danielle A. Bazer

    (Renaissance School of Medicine at Stony Brook University)

  • Ya-Wen Chen

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Wenbo Li

    (The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
    The University of Texas Health Science Center at Houston)

  • Chad D. Huff

    (The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
    The University of Texas MD Anderson Cancer Center)

  • Jay-Jiguang Zhu

    (The University of Texas Health Science Center at Houston)

  • Francesca Aguilo

    (Umea University
    Umea University)

  • Shih-Hwa Chiou

    (Taipei Veterans General Hospital
    National Yang Ming Chiao Tung University)

  • Nathan C. Boles

    (Neural Stem Cell Institute)

  • Chien-Chen Lai

    (National Chung Hsing University
    China Medical University
    National Chung Hsing University)

  • Mien-Chie Hung

    (China Medical University
    Asia University)

  • Zhongming Zhao

    (The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
    The University of Texas Health Science Center at Houston)

  • Eric L. Van Nostrand

    (Baylor College of Medicine)

  • Ruiying Zhao

    (The University of Texas Health Science Center at Houston)

  • Dung-Fang Lee

    (The University of Texas Health Science Center at Houston
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
    The University of Texas Health Science Center at Houston
    The University of Texas Health Science Center at Houston)

Abstract

N6-methyladenosine (m6A), one of the most prevalent mRNA modifications in eukaryotes, plays a critical role in modulating both biological and pathological processes. However, it is unknown whether mutant p53 neomorphic oncogenic functions exploit dysregulation of m6A epitranscriptomic networks. Here, we investigate Li-Fraumeni syndrome (LFS)-associated neoplastic transformation driven by mutant p53 in iPSC-derived astrocytes, the cell-of-origin of gliomas. We find that mutant p53 but not wild-type (WT) p53 physically interacts with SVIL to recruit the H3K4me3 methyltransferase MLL1 to activate the expression of m6A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m6A-marked tumor-suppressing transcripts, including CDKN2B and SPOCK2, and induces oncogenic reprogramming. Mutant p53 neoplastic behaviors are significantly impaired by genetic depletion of YTHDF2 or by pharmacological inhibition using MLL1 complex inhibitors. Our study reveals how mutant p53 hijacks epigenetic and epitranscriptomic machinery to initiate gliomagenesis and suggests potential treatment strategies for LFS gliomas.

Suggested Citation

  • An Xu & Mo Liu & Mo-Fan Huang & Yang Zhang & Ruifeng Hu & Julian A. Gingold & Ying Liu & Dandan Zhu & Chian-Shiu Chien & Wei-Chen Wang & Zian Liao & Fei Yuan & Chih-Wei Hsu & Jian Tu & Yao Yu & Taylor, 2023. "Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37398-9
    DOI: 10.1038/s41467-023-37398-9
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    References listed on IDEAS

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    1. Cen Zhang & Juan Liu & Yingjian Liang & Rui Wu & Yuhan Zhao & Xuehui Hong & Meihua Lin & Haiyang Yu & Lianxin Liu & Arnold J. Levine & Wenwei Hu & Zhaohui Feng, 2013. "Tumour-associated mutant p53 drives the Warburg effect," Nature Communications, Nature, vol. 4(1), pages 1-15, December.
    2. Jiajun Zhu & Morgan A. Sammons & Greg Donahue & Zhixun Dou & Masoud Vedadi & Matthäus Getlik & Dalia Barsyte-Lovejoy & Rima Al-awar & Bryson W. Katona & Ali Shilatifard & Jing Huang & Xianxin Hua & Ch, 2015. "Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth," Nature, Nature, vol. 525(7568), pages 206-211, September.
    3. Xiao Wang & Zhike Lu & Adrian Gomez & Gary C. Hon & Yanan Yue & Dali Han & Ye Fu & Marc Parisien & Qing Dai & Guifang Jia & Bing Ren & Tao Pan & Chuan He, 2014. "N6-methyladenosine-dependent regulation of messenger RNA stability," Nature, Nature, vol. 505(7481), pages 117-120, January.
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