TY  - JOUR
AU  - Suryo Rahmanto, Aldwin
AU  - Savov, Vasil
AU  - Brunner, Andrä
AU  - Bolin, Sara
AU  - Weishaupt, Holger
AU  - Malyukova, Alena
AU  - Rosén, Gabriela
AU  - Čančer, Matko
AU  - Hutter, Sonja
AU  - Sundström, Anders
AU  - Kawauchi, Daisuke
AU  - Jones, David
AU  - Spruck, Charles
AU  - Taylor, Michael D
AU  - Cho, Yoon-Jae
AU  - Pfister, Stefan
AU  - Kool, Marcel
AU  - Korshunov, Andrey
AU  - Swartling, Fredrik J
AU  - Sangfelt, Olle
TI  - FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma.
JO  - The EMBO journal
VL  - 35
IS  - 20
SN  - 1460-2075
CY  - Heidelberg
PB  - EMBO Press
M1  - DKFZ-2017-05461
SP  - 2192 - 2212
PY  - 2016
AB  - 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.
KW  - 4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidine-4-carboxamide (NLM Chemicals)
KW  - AZD2014 (NLM Chemicals)
KW  - AZD8186 (NLM Chemicals)
KW  - Aniline Compounds (NLM Chemicals)
KW  - Cell Cycle Proteins (NLM Chemicals)
KW  - Chromones (NLM Chemicals)
KW  - F-Box Proteins (NLM Chemicals)
KW  - Morpholines (NLM Chemicals)
KW  - Protein Kinase Inhibitors (NLM Chemicals)
KW  - Pyrimidines (NLM Chemicals)
KW  - Pyrroles (NLM Chemicals)
KW  - SOX9 Transcription Factor (NLM Chemicals)
KW  - SOX9 protein, human (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
KW  - Phosphatidylinositol 3-Kinases (NLM Chemicals)
KW  - MTOR protein, human (NLM Chemicals)
KW  - TOR Serine-Threonine Kinases (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-akt (NLM Chemicals)
KW  - Glycogen Synthase Kinase 3 (NLM Chemicals)
KW  - FBXW7 protein, human (NLM Chemicals)
KW  - Cisplatin (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27625374
C2  - pmc:PMC5069553
DO  - DOI:10.15252/embj.201693889
UR  - https://inrepo02.dkfz.de/record/130382
ER  -