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Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States.
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, TX, Houston, United States; University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, TX, Houston, United States.
College of Science, Harbin Institute of Technology (Shenzhen), Guangdong, Shenzhen, China.
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 1694Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer Nature , 2023. Vol. 14, no 1, article id 1694
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Medical Genetics Cell and Molecular Biology
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URN: urn:nbn:se:umu:diva-206456DOI: 10.1038/s41467-023-37398-9PubMedID: 36973285Scopus ID: 2-s2.0-85150958732OAI: oai:DiVA.org:umu-206456DiVA, id: diva2:1750375
Available from: 2023-04-13 Created: 2023-04-13 Last updated: 2023-04-13Bibliographically approved

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Aguilo, Francesca

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Wallenberg Centre for Molecular Medicine at Umeå University (WCMM)Department of Molecular Biology (Faculty of Medicine)
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