2. Academic Validation
  3. Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation

Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation

  • Nat Commun. 2023 Mar 27;14(1):1694. doi: 10.1038/s41467-023-37398-9.
An Xu # 1,  Mo Liu # 1,  Mo-Fan Huang 1 2,  Yang Zhang 3,  Ruifeng Hu 4,  Julian A Gingold 5,  Ying Liu 1,  Dandan Zhu 1,  Chian-Shiu Chien 6 7,  Wei-Chen Wang 8,  Zian Liao 9,  Fei Yuan 9,  Chih-Wei Hsu 10,  Jian Tu 1,  Yao Yu 11,  Taylor Rosen 1,  Feng Xiong 12,  Peilin Jia 4,  Yi-Ping Yang 6 7,  Danielle A Bazer 13,  Ya-Wen Chen 14 15 16 17,  Wenbo Li 2 12,  Chad D Huff 2 11,  Jay-Jiguang Zhu 18,  Francesca Aguilo 19 20,  Shih-Hwa Chiou 6 7,  Nathan C Boles 21,  Chien-Chen Lai 8 22 23,  Mien-Chie Hung 24 25,  Zhongming Zhao 2 4,  Eric L Van Nostrand 9,  Ruiying Zhao 26,  Dung-Fang Lee 27 28 29 30
Affiliations

Affiliations

  • 1 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
  • 2 The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
  • 3 College of Science, Harbin Institute of Technology (Shenzhen), Shenzhen, Guangdong, 518055, China.
  • 4 Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
  • 5 Department of Obstetrics & Gynecology and Women's Health, Einstein/Montefiore Medical Center, Bronx, NY, 10461, USA.
  • 6 Department of Medical Research, Taipei Veterans General Hospital, Taipei, 112, Taiwan.
  • 7 College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.
  • 8 Institute of Molecular Biology, National Chung Hsing University, Taichung, 40227, Taiwan.
  • 9 Verna & Marrs McLean Department of Biochemistry & Molecular Biology and Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 10 Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 11 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 12 Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
  • 13 Department of Neurology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, 11794, USA.
  • 14 Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 15 Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 16 Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 17 Institute for Airway Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 18 Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
  • 19 Wallenberg Centre for Molecular Medicine (WCMM), Umea University, SE-901 85, Umea, Sweden.
  • 20 Department of Molecular Biology, Umea University, SE-901 85, Umea, Sweden.
  • 21 Neural Stem Cell Institute, Rensselaer, NY, 12144, USA.
  • 22 Graduate institute of Chinese Medical Science, China Medical University, Taichung, 40402, Taiwan.
  • 23 Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, 40227, Taiwan.
  • 24 Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, and Office of the President, China Medical University, Taichung, 404, Taiwan.
  • 25 Department of Biotechnology, Asia University, Taichung, 413, Taiwan.
  • 26 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. [email protected].
  • 27 Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. [email protected].
  • 28 The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA. [email protected].
  • 29 Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. [email protected].
  • 30 Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. [email protected].
  • # Contributed equally.
PMID: 36973285 DOI: 10.1038/s41467-023-37398-9
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.

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