FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma

• Aldwin Suryo Rahmanto ^[5] ; Vasil Savov ^[6] ; Andrä Brunner ^[5] ; Sara Bolin ^[6] ; Holger Weishaupt ^[6] ; Alena Malyukova ^[5] ; Gabriela Rosén ^[6] ; Matko Čančer ^[6] ; Sonja Hutter ^[7] ; Anders Sundström ^[6] ; Daisuke Kawauchi ^[1] ; David TW Jones ^[1] ; Charles Spruck ^[2] ; Michael D Taylor ^[3] ; Yoon‐Jae Cho ^[4] ; Stefan M Pfister ^[1] ; Marcel Kool ^[1] ; Andrey Korshunov ^[1] ; Fredrik J Swartling ^[6] ; Olle Sangfelt ^[5]
  1. [1] German Cancer Research Center

     German Cancer Research Center

     Stadtkreis Heidelberg, Alemania

     
  2. [2] Sanford Burnham Prebys Medical Discovery Institute

     Sanford Burnham Prebys Medical Discovery Institute

     Estados Unidos

     
  3. [3] Hospital for Sick Children

     Hospital for Sick Children

     Canadá

     
  4. [4] Stanford University School of Medicine

     Stanford University School of Medicine

     Estados Unidos

     
  5. [5] 1 Department of Cell and Molecular Biology Karolinska Institutet Stockholm Sweden
  6. [6] 2 Department of Immunology, Genetics and Pathology Science for Life Laboratory Rudbeck Laboratory Uppsala University Uppsala Sweden
  7. [7] 2 Department of Immunology, Genetics and Pathology Science for Life Laboratory Rudbeck Laboratory Uppsala University Uppsala Sweden; 3 German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) Heidelberg Germany

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 35, Nº. 20, 2016, págs. 2192-2212
• Idioma: inglés
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• Resumen

  • SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here, we show that SOX9 is a substrate of FBW7, a tumor suppressor, and a SCF (SKP1/CUL1/F‐box)‐type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase and consequently degraded by SCFFBW 7α. Failure to degrade SOX9 promotes migration, metastasis, and treatment resistance in medulloblastoma, one of the most common childhood brain tumors. FBW7 is either mutated or downregulated in medulloblastoma, and in cases where FBW7 mRNA levels are low, SOX9 protein is significantly elevated and this phenotype is associated with metastasis at diagnosis and poor patient outcome. Transcriptional profiling of medulloblastoma cells expressing a degradation‐resistant SOX9 mutant reveals activation of pro‐metastatic genes and genes linked to cisplatin resistance. Finally, we show that pharmacological inhibition of PI3K/AKT/mTOR pathway activity destabilizes SOX9 in a GSK3/FBW7‐dependent manner, rendering medulloblastoma cells sensitive to cytostatic treatment.