[en] 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.
Research center :
GIGA
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Jeschke, Jana; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Collignon, Evelyne ; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Al Wardi, Clémence; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Krayem, Mohammad; Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, ULB, Brussels, Belgium
Bizet, Martin; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Jia, Yan; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium ; Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Wimana, Zéna; Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, ULB, Brussels, Belgium ; Department of Nuclear Medicine, Institut Jules Bordet, ULB, Brussels, Belgium
Calonne, Emilie; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Hassabi, Bouchra; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Morandini, Renato; Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, ULB, Brussels, Belgium
Deplus, Rachel; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Putmans, Pascale; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Dube, Gaurav; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Singh, Nitesh Kumar; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium
Koch, Alexander; Department of Pathology, Maastricht UMC, Maastricht, the Netherlands
Shostak, Kateryna ; Université de Liège - ULiège > GIGA > GIGA Stem Cells - Medical Chemistry
Rizzotto, Lara; Trace, LKI Leuven Cancer Institute, KU Leuven, Leuven, Belgium
Ross, Robert L; Rieveschl Laboratories for Mass Spectrometry, Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA
Desmedt, Christine ; Breast Cancer Translational Research Laboratory, Institut Jules Bordet, U-CRC, ULB, Brussels, Belgium
Bareche, Yacine ; Breast Cancer Translational Research Laboratory, Institut Jules Bordet, U-CRC, ULB, Brussels, Belgium
Rothé, Françoise; Breast Cancer Translational Research Laboratory, Institut Jules Bordet, U-CRC, ULB, Brussels, Belgium
Lehmann-Che, Jacqueline ; Pathophysiology of Breast Cancer Team, Université de Paris, INSERM U976, HIPI, Paris, France ; Breast Disease Unit and Molecular Oncology Unit, AP-HP, Hôpital Saint-Louis, Paris, France
Duterque-Coquillaud, Martine; Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-UMR-S 1277, CANTHER, Lille, France
Leroy, Xavier; Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020-UMR-S 1277, CANTHER, Lille, France ; Department of Pathology, CHU Lille, Université Lille, Lille, France
Menschaert, Gerben; Biobix, Laboratory of Bioinformatics and Computational Genomics, Ghent University, Ghent, Belgium
Teixeira, Luis ; Pathophysiology of Breast Cancer Team, Université de Paris, INSERM U976, HIPI, Paris, France ; Breast Disease Unit and Molecular Oncology Unit, AP-HP, Hôpital Saint-Louis, Paris, France
Guo, Mingzhou; Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing, China
Limbach, Patrick A; Rieveschl Laboratories for Mass Spectrometry, Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA
Close, Pierre ; Université de Liège - ULiège > GIGA > GIGA Stem Cells - Cancer Signaling
CHARIOT, Alain ; Centre Hospitalier Universitaire de Liège - CHU > > Service de chimie clinique
Leucci, Eleonora; Trace, LKI Leuven Cancer Institute, KU Leuven, Leuven, Belgium ; Laboratory of RNA Cancer Biology, Department of Oncology, LKI, KU Leuven, Leuven, Belgium
Ghanem, Ghanem; Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, ULB, Brussels, Belgium
Yuan, Bi-Feng ; College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, China
Sotiriou, Christos ; Breast Cancer Translational Research Laboratory, Institut Jules Bordet, U-CRC, ULB, Brussels, Belgium
Marine, Jean-Christophe; Laboratory for Molecular Cancer Biology, VIB, KU Leuven, Leuven, Belgium ; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
Fuks, François ; Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université Libre de Bruxelles (ULB), Brussels, Belgium. ffuks@ulb.ac.be ; WELBIO, Université Libre de Bruxelles (ULB), Brussels, Belgium. ffuks@ulb.ac.be
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Télévie [BE] Fondation contre le Cancer [BE] WELBIO - Walloon Excellence in Life Sciences and Biotechnology [BE]
Funding text :
J.J. was supported by the Belgian ‘Fonds de la Recherche Scientifique’ (FNRS) postdoctoral fellowship, E. Collignon was supported by the L’Oréal ‘For Women In Science’ fellowship and by the Belgian FNRS and Y.J. was supported by the China Scholarship Council (CSC) postdoctoral fellowship. C.A.W., M.B., B.H. and G.D. were supported by the Belgian FNRS. N.K.S. was supported by the ULB Foundation. F.F. is a ULB Professor. F.F.’s lab was funded by grants from the FNRS and Télévie, the ‘Action de Recherche Concertée’ (ARC; AUWB-2018-2023 ULB-No 7), Wallon Region grants (U-CAN-REST, INTREPID), an FNRS Welbio grant, the ULB Foundation and the Belgian Foundation Against Cancer (FCC 2016-086 FAF-F/2016/872). P.C. and A.C. are Senior Research Associate and Research Director at the FNRS, respectively. C.S. is a research director at the FNRS and his lab is supported by grants from the FNRS. P.A.L. was supported by the National Institutes of Health (GM 058843). Trace is supported by the ‘Belgian Foundation Against Cancer’ and, as a part of the EurOPDX infrastructure, by EDIReX a Horizon 2020 grant agreement 731105. PET–CT acquisition was performed at the nuMix-CMMI, which is supported by the European Regional Development Fund (ERDF) and the Walloon Region.
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