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EMBO J. 2016 Oct 17;35(20):2192-2212. Epub 2016 Sep 13.

FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma.

Author information

1
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
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.
4
Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA.
5
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
6
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
7
Department of Pediatric Hematology and Oncology, University Hospital, Heidelberg, Germany.
8
Department of Neuropathology, University Hospital, Heidelberg, Germany.
9
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden fredrik.swartling@igp.uu.se olle.sangfelt@ki.se.
10
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden fredrik.swartling@igp.uu.se olle.sangfelt@ki.se.

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 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.

KEYWORDS:

FBW7; SOX9; cisplatin; medulloblastoma; metastasis

PMID:
27625374
PMCID:
PMC5069553
DOI:
10.15252/embj.201693889
[Indexed for MEDLINE]
Free PMC Article

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