Downregulation of the FTO m6A RNA demethylase promotes EMT-mediated progression of epithelial tumors and sensitivity to Wnt inhibitors.

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 N6-methyladenosine (m6A), 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 m6A 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.

• Authors: Jana Jeschke, Evelyne Collignon, Clémence Al Wardi, Mohammad Krayem, Martin Bizet, Yan Jia, Soizic Garaud, Zéna 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 Desmedt, Yacine Bareche, Françoise Rothé, 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, François Fuks
• Journal: Nature cancer (Nat Cancer) Vol. 2 Issue 6 Pg. 611-628 (06 2021) ISSN: 2662-1347 [Electronic] England
• PMID: 35121941 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• RNA
• FTO protein, mouse
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO
• FTO protein, human

Topics

• Alpha-Ketoglutarate-Dependent Dioxygenase FTO (genetics)
• Animals
• Down-Regulation (genetics)
• Epithelial-Mesenchymal Transition (genetics)
• Humans
• Mice
• Neoplasms, Glandular and Epithelial
• RNA