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

N-6-methyladenosine (m(6)A) of mRNAs modulated by the METTL3-METTL14-WTAP-RBM15 methyltransferase complex and m(6)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(6)A RIP-seq analysis revealed that FTO-IT1 knockout increased mRNA m(6)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(6)A methylation, and stability of p53 target mRNAs. Therapeutic depletion of FTO-IT1 restored mRNA m(6)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(6)A methyltransferase complex and p53 tumor suppression signaling and nominates FTO-IT1 as a potential therapeutic target of cancer.

Automated summary

The FTO-IT1 lncRNA is upregulated in wild-type p53-expressing prostate cancer patients and is associated with poor survival. It acts by binding to RBM15 and inhibiting the methylation and stability of p53 target mRNAs. Therapeutic depletion of FTO-IT1 restores mRNA m(6)A level and expression of p53 target genes, leading to inhibition of tumor growth.