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- Title
Rewired m<sup>6</sup>A epitranscriptomic networks link mutant p53 to neoplastic transformation.
- Authors
Xu, An; Liu, Mo; Huang, Mo-Fan; Zhang, Yang; Hu, Ruifeng; Gingold, Julian A.; Liu, Ying; Zhu, Dandan; Chien, Chian-Shiu; Wang, Wei-Chen; Liao, Zian; Yuan, Fei; Hsu, Chih-Wei; Tu, Jian; Yu, Yao; Rosen, Taylor; Xiong, Feng; Jia, Peilin; Yang, Yi-Ping; Bazer, Danielle A.
- 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. The dysregulation of the m6A epitranscriptomic networks have been reported to contribute to the development of gliomas. Here, the authors utilize induced pluripotent stem cell-derived astrocytes with a p53 mutation and demonstrate that mutant p53 upregulates the m6A reader YTHDF2, resulting in the initiation of gliomas.
- Subjects
LI-Fraumeni syndrome; GLIOMAS; ADENOSINES; METHYLTRANSFERASES; ASTROCYTES
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-37398-9