A lncRNA from the FTO locus acts as a suppressor of the m 6 A writer complex and p53 tumor suppression signaling

N -methyladenosine (m A) of mRNAs modulated by the METTL3-METTL14-WTAP-RBM15 methyltransferase complex and m A 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 posi...

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Published in:Molecular cell 2023-08, Vol.83 (15), p.2692
Main Authors: Zhang, Jianong, Wei, Jiangbo, Sun, Rui, Sheng, Haoyue, Yin, Kai, Pan, Yunqian, Jimenez, Rafael, Chen, Sujun, Cui, Xiao-Long, Zou, Zhongyu, Yue, Zhiying, Emch, Michael J, Hawse, John R, Wang, Liguo, He, Housheng Hansen, Xia, Shujie, Han, Bangmin, He, Chuan, Huang, Haojie
Format: Article
Language:English
Subjects:
Adenosine - metabolism
Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics
Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism
Animals
Male
Methyltransferases - genetics
Methyltransferases - metabolism
Mice
Neoplasms
RNA, Long Noncoding - genetics
RNA, Messenger - genetics
Tumor Suppressor Protein p53 - genetics
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Summary:N -methyladenosine (m A) of mRNAs modulated by the METTL3-METTL14-WTAP-RBM15 methyltransferase complex and m A 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). m A RIP-seq analysis revealed that FTO-IT1 knockout increased mRNA m A 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, m A methylation, and stability of p53 target mRNAs. Therapeutic depletion of FTO-IT1 restored mRNA m A 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 m A methyltransferase complex and p53 tumor suppression signaling and nominates FTO-IT1 as a potential therapeutic target of cancer.
ISSN:1097-4164