title: SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development.
abstract: Skp1-Cul1-F-box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma-associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17-mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17-Sufu axis in the pathogenesis of medulloblastoma.
authors.affiliation: Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Madalina
authors.initials: M
authors.lastname: Raducu
authors.affiliation: Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Ella
authors.initials: E
authors.lastname: Fung
authors.affiliation: Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Serres
authors.affiliation: Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Infante
authors.affiliation: Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Barberis
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Roman
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Bristow
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Marie-Laëtitia
authors.initials: ML
authors.lastname: Thézénas
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Csaba
authors.initials: C
authors.lastname: Finta
authors.affiliation: Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Christianson
authors.affiliation: Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Nicola R
authors.initials: NR
authors.lastname: Sibson
authors.affiliation: Department of Molecular Medicine, University "La Sapienza", Rome, Italy Pasteur Institute/Cenci Bolognetti Foundation Sapienza University, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.affiliation: Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Rune
authors.initials: R
authors.lastname: Toftgård
authors.affiliation: Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK vincenzo.dangiolella@oncology.ox.ac.uk.
authors.forename: Vincenzo
authors.identifier: 0000-0001-8365-9094
authors.initials: V
authors.lastname: D'Angiolella
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004195:Disease Models, Animal; D044783:F-Box Proteins / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000473:pathology*; D051379:Mice; D011499:Protein Processing, Post-Translational; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; C532335:FBXL17 protein, human; D053823:Hedgehog Proteins; D012097:Repressor Proteins; C490764:SUFU protein, human
keywords: Fbxl17; F‐box protein; Hedgehog signaling; Sufu; medulloblastoma