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Rewired m⁶A epitranscriptomic networks link mutant p53 to neoplastic transformation.

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.

SUBMITTER: Xu A

PROVIDER: S-EPMC10042811 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation.

Xu An A Liu Mo M Huang Mo-Fan MF Zhang Yang Y Hu Ruifeng R Gingold Julian A JA Liu Ying Y Zhu Dandan D Chien Chian-Shiu CS Wang Wei-Chen WC Liao Zian Z Yuan Fei F Hsu Chih-Wei CW Tu Jian J Yu Yao Y Rosen Taylor T Xiong Feng F Jia Peilin P Yang Yi-Ping YP Bazer Danielle A DA Chen Ya-Wen YW Li Wenbo W Huff Chad D CD Zhu Jay-Jiguang JJ Aguilo Francesca F Chiou Shih-Hwa SH Boles Nathan C NC Lai Chien-Chen CC Hung Mien-Chie MC Zhao Zhongming Z Van Nostrand Eric L EL Zhao Ruiying R Lee Dung-Fang DF

Nature communications 20230327 1

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 muta ...[more]

PMID: 36973285

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Rewired m⁶A epitranscriptomic networks link mutant p53 to neoplastic transformation.

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Rewired m<sup>6</sup>A epitranscriptomic networks link mutant p53 to neoplastic transformation.

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