Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation

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 Rosen, Feng Xiong, Peilin Jia, Yi-Ping Yang, Danielle A. Bazer, Ya-Wen Chen, Wenbo Li, Chad D. Huff, Jay-Jiguang Zhu, Francesca Aguilo, Shih-Hwa Chiou, Nathan C. Boles, Chien-Chen Lai, Mien-Chie Hung, Zhongming Zhao, Eric L. Van Nostrand, Ruiying Zhao () and Dung-Fang Lee ()
Additional contact information
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
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
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
Danielle A. Bazer: Renaissance School of Medicine at Stony Brook University
Ya-Wen Chen: Icahn School of Medicine at Mount Sinai
Wenbo Li: The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
Chad D. Huff: The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
Jay-Jiguang Zhu: The University of Texas Health Science Center at Houston
Francesca Aguilo: Umea University
Shih-Hwa Chiou: Taipei Veterans General Hospital
Nathan C. Boles: Neural Stem Cell Institute
Chien-Chen Lai: National Chung Hsing University
Mien-Chie Hung: China Medical University
Zhongming Zhao: The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
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

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37398-9

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