title: Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine.
abstract: Tumor initiation in the intestine can rapidly occur from Lgr5(+) crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5(+) cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5(+)/Dclk1(+) cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1(+) cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine.
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium Laboratory of Medical Chemistry, University of Liège, 4000 Liège, Belgium GIGA-Signal Transduction, University of Liège, 4000 Liège, Belgium.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ladang
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium Laboratory of Cancer Signaling, University of Liège, 4000 Liège, Belgium GIGA-Signal Transduction, University of Liège, 4000 Liège, Belgium.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rapino
authors.affiliation: Institut für Pathologie, University Hospital Cologne, 50937 Cologne, Germany.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.affiliation: Institut für Pathologie, University Hospital Cologne, 50937 Cologne, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Tharun
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium Laboratory of Medical Chemistry, University of Liège, 4000 Liège, Belgium GIGA-Signal Transduction, University of Liège, 4000 Liège, Belgium.
authors.forename: Kateryna
authors.initials: K
authors.lastname: Shostak
authors.affiliation: Unité de Recherche en Physiologie Moléculaire-Laboratoire de Génétique Moléculaire, University of Namur, 5000 Namur, Belgium.
authors.forename: Damien
authors.initials: D
authors.lastname: Hermand
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium Laboratory of Cancer Signaling, University of Liège, 4000 Liège, Belgium GIGA-Signal Transduction, University of Liège, 4000 Liège, Belgium.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Delaunay
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium Laboratory of Medical Chemistry, University of Liège, 4000 Liège, Belgium GIGA-Signal Transduction, University of Liège, 4000 Liège, Belgium.
authors.forename: Iva
authors.initials: I
authors.lastname: Klevernic
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium Laboratory of Medical Chemistry, University of Liège, 4000 Liège, Belgium GIGA-Signal Transduction, University of Liège, 4000 Liège, Belgium.
authors.forename: Zheshen
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium Laboratory of Medical Chemistry, University of Liège, 4000 Liège, Belgium GIGA-Signal Transduction, University of Liège, 4000 Liège, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jacques
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium Laboratory of Cancer Signaling, University of Liège, 4000 Liège, Belgium GIGA-Signal Transduction, University of Liège, 4000 Liège, Belgium.
authors.forename: Diane
authors.initials: D
authors.lastname: Jamart
authors.affiliation: Unité de Recherche en Physiologie Moléculaire-Laboratoire de Génétique Moléculaire, University of Namur, 5000 Namur, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Migeot
authors.affiliation: Institut für Pathologie, University Hospital Cologne, 50937 Cologne, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Florin
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium Laboratory of Medical Chemistry, University of Liège, 4000 Liège, Belgium GIGA-Signal Transduction, University of Liège, 4000 Liège, Belgium.
authors.forename: Serkan
authors.initials: S
authors.lastname: Göktuna
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium GIGA Neurosciences, University of Liège, 4000 Liège, Belgium.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Malgrange
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow G61 1BD, Scotland, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium GIGA Neurosciences, University of Liège, 4000 Liège, Belgium Walloon Excellence in Life Sciences and Biotechnology, 1300 Wavre, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Institut für Pathologie, University Hospital Cologne, 50937 Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium Laboratory of Cancer Signaling, University of Liège, 4000 Liège, Belgium GIGA-Signal Transduction, University of Liège, 4000 Liège, Belgium pierre.close@ulg.ac.be alain.chariot@ulg.ac.be.
authors.forename: Pierre
authors.initials: P
authors.lastname: Close
authors.affiliation: Interdisciplinary Cluster for Applied Genoproteomics, University of Liège, 4000 Liège, Belgium Laboratory of Medical Chemistry, University of Liège, 4000 Liège, Belgium GIGA-Signal Transduction, University of Liège, 4000 Liège, Belgium Walloon Excellence in Life Sciences and Biotechnology, 1300 Wavre, Belgium pierre.close@ulg.ac.be alain.chariot@ulg.ac.be.
authors.forename: Alain
authors.initials: A
authors.lastname: Chariot
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000089742:Doublecortin-Like Kinases; D015870:Gene Expression / Q000528:radiation effects; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000503:physiopathology* / Q000528:radiation effects; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009924:Organ Culture Techniques; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C493597:Lgr5 protein, mouse; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D051153:Wnt Proteins; C538729:ELP3 protein, human; C000606524:Elp3 protein, mouse; D051548:Histone Acetyltransferases; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases