A lncRNA from the FTO locus acts as a suppressor of the m6A writer complex and p53 tumor suppression signaling
Jianong Zhang, Jiangbo Wei, Rui Sun, Haoyue Sheng, Kai Yin, Yunqian Pan, Rafael E. Jiménez, Sujun Chen, Xiao‐Long Cui, Zhongyu Zou, Zhiying Yue, Michael J. Emch, John R. Hawse, Liguo Wang, Housheng Hansen He, Shujie Xia, Bangmin Han, Chuan He, Haojie Huang
Abstract
N6-methyladenosine (m6A) of mRNAs modulated by the METTL3-METTL14-WTAP-RBM15 methyltransferase complex and m6A demethylases such as FTO play important roles in regulating mRNA stability, splicing, and translation. Here, we demonstrate that FTO-IT1 long noncoding RNA (lncRNA) was upregulated and positively correlated with poor survival of patients with wild-type p53-expressing prostate cancer (PCa). m6A RIP-seq analysis revealed that FTO-IT1 knockout increased mRNA m6A methylation of a subset of p53 transcriptional target genes (e.g., FAS, TP53INP1, and SESN2) and induced PCa cell cycle arrest and apoptosis. We further showed that FTO-IT1 directly binds RBM15 and inhibits RBM15 binding, m6A methylation, and stability of p53 target mRNAs. Therapeutic depletion of FTO-IT1 restored mRNA m6A level and expression of p53 target genes and inhibited PCa growth in mice. Our study identifies FTO-IT1 lncRNA as a bona fide suppressor of the m6A methyltransferase complex and p53 tumor suppression signaling and nominates FTO-IT1 as a potential therapeutic target of cancer.