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. BazerYa 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*, Dung Fang Lee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish
Article number1694
JournalNature Communications
Issue number1
StatePublished - Dec 2023


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