Journal Article

DKFZ-2017-05461

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma.

Suryo Rahmanto, A. ; Savov, V. ; Brunner, A. ; Bolin, S. ; Weishaupt, H. ; Malyukova, A. ; Rosén, G. ; Čančer, M. ; Hutter, S.DKFZ* ; Sundström, A. ; Kawauchi, D.DKFZ* ; Jones, D.DKFZ* ; Spruck, C. ; Taylor, M. D. ; Cho, Y.-J. ; Pfister, S.DKFZ* ; Kool, M.DKFZ* ; Korshunov, A.DKFZ* ; Swartling, F. J. ; Sangfelt, O.

2016
EMBO Press Heidelberg

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Please use a persistent id in citations: doi:10.15252/embj.201693889

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)(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.

Keyword(s): 4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidine-4-carboxamide ; AZD2014 ; AZD8186 ; Aniline Compounds ; Cell Cycle Proteins ; Chromones ; F-Box Proteins ; Morpholines ; Protein Kinase Inhibitors ; Pyrimidines ; Pyrroles ; SOX9 Transcription Factor ; SOX9 protein, human ; Ubiquitin-Protein Ligases ; Phosphatidylinositol 3-Kinases ; MTOR protein, human ; TOR Serine-Threonine Kinases ; Proto-Oncogene Proteins c-akt ; Glycogen Synthase Kinase 3 ; FBXW7 protein, human ; Cisplatin

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Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)
2. KKE Neuropathologie (G380)
3. DKTK Heidelberg (L101)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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