Downregulation of the FTO m(6)A RNA demethylase promotes EMT-mediated progression of epithelial tumors and sensitivity to Wnt inhibitors

Jana Jeschke, Evelyne Collignon, Clemence Al Wardi, Mohammad Krayem, Martin Bizet, Yan Jia, Soizic Garaud, Zena Wimana, Emilie Calonne, Bouchra Hassabi, Renato Morandini, Rachel Deplus, Pascale Putmans, Gaurav Dube, Nitesh Kumar Singh, Alexander Koch, Kateryna Shostak, Lara Rizzotto, Robert L. Ross, Christine DesmedtYacine Bareche, Francoise Rothe, Jacqueline Lehmann-Che, Martine Duterque-Coquillaud, Xavier Leroy, Gerben Menschaert, Luis Teixeira, Mingzhou Guo, Patrick A. Limbach, Pierre Close, Alain Chariot, Eleonora Leucci, Ghanem Ghanem, Bi-Feng Yuan, Karen Willard-Gallo, Christos Sotiriou, Jean-Christophe Marine, Francois Fuks*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Web of Science)

Abstract

Post-transcriptional modifications of RNA constitute an emerging regulatory layer of gene expression. The demethylase fat mass- and obesity-associated protein (FTO), an eraser of N-6-methyladenosine (m(6)A), has been shown to play a role in cancer, but its contribution to tumor progression and the underlying mechanisms remain unclear. Here, we report widespread FTO downregulation in epithelial cancers associated with increased invasion, metastasis and worse clinical outcome. Both in vitro and in vivo, FTO silencing promotes cancer growth, cell motility and invasion. In human-derived tumor xenografts (PDXs), FTO pharmacological inhibition favors tumorigenesis. Mechanistically, we demonstrate that FTO depletion elicits an epithelial-to-mesenchymal transition (EMT) program through increased m(6)A and altered 3-end processing of key mRNAs along the Wnt signaling cascade. Accordingly, FTO knockdown acts via EMT to sensitize mouse xenografts to Wnt inhibition. We thus identify FTO as a key regulator, across epithelial cancers, of Wnt-triggered EMT and tumor progression and reveal a therapeutically exploitable vulnerability of FTO-low tumors.Fuks and colleagues report that downregulation of the FTO m(6)A RNA demethylase activates the Wnt pathway, promoting EMT-mediated progression of epithelial tumors and conferring sensitivity to Wnt inhibitors.

Original languageEnglish
Pages (from-to)611-+
Number of pages30
JournalNature Cancer
Volume2
Issue number6
DOIs
Publication statusPublished - Jun 2021

Keywords

  • BREAST-CANCER
  • MESSENGER-RNAS
  • METHYLATION
  • EXPRESSION
  • ACTIVATION
  • REVEALS
  • MASS
  • N6-METHYLADENOSINE
  • DIFFERENTIATION
  • POLYADENYLATION

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