SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

• Madalina Raducu ^[2] ; Ella Fung ^[2] ; Sébastien Serres ^[2] ; Paola Infante ^[3] ; Alessandro Barberis ^[2] ; Roman Fischer ^[1] ; Claire Bristow ^[2] ; Marie‐Laëtitia Thézénas ^[1] ; Csaba Finta ^[4] ; John C Christianson ^[5] ; Francesca M Buffa ^[2] ; Benedikt M Kessler ^[1] ; Nicola R Sibson ^[2] ; Lucia Di Marcotullio ^[6] ; Rune Toftgård ^[4] ; Vincenzo D'Angiolella ^[2]
  1. [1] University of Oxford

     University of Oxford

     Oxford District, Reino Unido

     
  2. [2] 1 Cancer Research UK and Medical Research Council Institute for Radiation Oncology Department of Oncology University of Oxford Oxford UK
  3. [3] 2 Center for Life NanoScience@Sapienza Istituto Italiano di Tecnologia Rome Italy
  4. [4] 4 Department of Biosciences and Nutrition Center for Innovative Medicine Karolinska Institutet Huddinge Sweden
  5. [5] 5 Ludwig Institute for Cancer Research University of Oxford Oxford UK
  6. [6] 6 Department of Molecular Medicine University “La Sapienza” Rome Italy; 7 Pasteur Institute/Cenci Bolognetti Foundation Sapienza University Rome Italy

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 35, Nº. 13, 2016, págs. 1400-1416
• Idioma: inglés
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  • 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.