A lncRNA from the FTO locus acts as a suppressor of the m6A writer complex and p53 tumor suppression signaling

Mol Cell. 2023 Aug 3;83(15):2692-2708.e7. doi: 10.1016/j.molcel.2023.06.024. Epub 2023 Jul 20.

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.

Keywords: FTO; FTO-IT1; METTL14; METTL3; N(6)-methyladenosine; RBM15; lncRNA; m(6)A; p53; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • 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

Substances

  • RNA, Long Noncoding
  • Tumor Suppressor Protein p53
  • Adenosine
  • RNA, Messenger
  • Methyltransferases
  • FTO protein, mouse
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO