FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma

Aldwin Suryo Rahmanto, Vasil Savov, Andrä Brunner, Sara Bolin, Holger Weishaupt, Alena Malyukova, Gabriela Rosén, Matko Čančer, Sonja Hutter, Anders Sundström, Daisuke Kawauchi, David T.W. Jones, Charles Spruck, Michael D. Taylor, Yoon-Jae Cho, Stefan M. Pfister, Marcel Kool, Andrey Korshunov, Fredrik J. Swartling, Olle Sangfelt

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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 SCF FBW . 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.

Original languageEnglish (US)
Pages (from-to)2192-2212
Number of pages21
JournalEMBO Journal
Volume35
Issue number20
DOIs
StatePublished - Oct 17 2016
Externally publishedYes

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Keywords

  • cisplatin
  • FBW7
  • medulloblastoma
  • metastasis
  • SOX9

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Suryo Rahmanto, A., Savov, V., Brunner, A., Bolin, S., Weishaupt, H., Malyukova, A., Rosén, G., Čančer, M., Hutter, S., Sundström, A., Kawauchi, D., Jones, D. T. W., Spruck, C., Taylor, M. D., Cho, Y-J., Pfister, S. M., Kool, M., Korshunov, A., Swartling, F. J., & Sangfelt, O. (2016). FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma. EMBO Journal, 35(20), 2192-2212. https://doi.org/10.15252/embj.201693889