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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 27, 2023
- Source ID
- 10.1038/s41467-023-37398-9
Entities
People
- An Xu
- Chad D. Huff
- Chian-Shiu Chien
- Chien-Chen Lai
- Chih-Wei Hsu
- Dandan Zhu
- Danielle Bazer
- Dung-Fang Lee
- Eric Van Nostrand
- Fei Yuan
- Feng Xiong
- Francesca Aguilo
- Jay-Jiguang Zhu
- Jian Tu
- Julian Gingold
- Mien-Chie Hung
- Mo Liu
- Mo-Fan Huang
- Nathan C. Boles
- Peilin Jia
- Ruifeng Hu
- Ruiying Zhao
- Shih-hwa Chiou
- Taylor Rosen
- Wei-chen Wang
- Wenbo Li
- Ya-Wen Chen
- Yang Zhang
- Yao Yu
- Yi-ping Yang
- Ying Liu
- Zhongming Zhao
- Zian Liao
Organizations
- Cancer Prevention and Research Institute of Texas
- National Cancer Institute
- United States Army
- United States Department of Health and Human Services
- United States National Library of Medicine