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 Bazer, Ya‐Wen Chen, Wenbo Li, Chad D. Huff, Jay‐Jiguang Zhu, Francesca Aguiló, Shih‐Hwa Chiou, Nathan C. Boles, Chien‐Chen Lai, Mien‐Chie Hung, Zhongming Zhao, Eric L. Van Nostrand, Ruiying Zhao, Dung‐Fang Lee
Abstract
Abstract N6-methyladenosine (m 6 A), 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 m 6 A 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 m 6 A reader YTHDF2, culminating in an oncogenic phenotype. Aberrant YTHDF2 upregulation markedly hampers expression of multiple m 6 A-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.