FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma

• Verfasst von: Rahmanto, Aldwin Suryo [VerfasserIn]
• Verfasst von: Jones, David T. W. [VerfasserIn]
• Verfasst von: Pfister, Stefan [VerfasserIn]
• Verfasst von: Kool, Marcel [VerfasserIn]
• Verfasst von: Korshunov, Andrey [VerfasserIn]
• Titel: FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma
• Verf.angabe: Aldwin Suryo Rahmanto, Vasil Savov, Andrä Brunner, Sara Bolin, Holger Weishaupt, Alena Malyukova, Gabriela Rosén, Matko Čančer, Sonja Hutter, Anders Sundström, Daisuke Kawauchi, David TW Jones, Charles Spruck, Michael D Taylor, Yoon‐Jae Cho, Stefan M Pfister, Marcel Kool, Andrey Korshunov, Fredrik J Swartling, Olle Sangfelt
• E-Jahr: 2016
• Jahr: 13 September 2016
• Umfang: 21 S.
• Fussnoten: Gesehen am 06.11.2017
• Titel Quelle: Enthalten in: European Molecular Biology OrganizationThe EMBO journal
• Ort Quelle: [London] : Nature Publishing Group UK, 1982
• Jahr Quelle: 2016
• Band/Heft Quelle: 35(2016), 20, Seite 2192-2212
• ISSN Quelle: 1460-2075
• DOI: doi:10.15252/embj.201693889
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1565057511

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 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.