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.
Molecular cell. 2023 Jul 20 [Epub]
Jianong Zhang, Jiangbo Wei, Rui Sun, Haoyue Sheng, Kai Yin, Yunqian Pan, Rafael Jimenez, 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
Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Hongkou District, Shanghai 200080, China. Electronic address: ., Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA., Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA., Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang 212002, China., Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA., Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada., Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China., Department of Computation Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA., Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 100 Haining Road, Hongkou District, Shanghai 200080, China., Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. Electronic address: ., Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address: .