@article{0c85f90f83e548458b8a5db15408fc77,
title = "FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma",
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.",
keywords = "FBW7, SOX9, cisplatin, medulloblastoma, metastasis",
author = "{Suryo Rahmanto}, Aldwin and Vasil Savov and Andr{\"a} Brunner and Sara Bolin and Holger Weishaupt and Alena Malyukova and Gabriela Ros{\'e}n and Matko {\v C}an{\v c}er and Sonja Hutter and Anders Sundstr{\"o}m and Daisuke Kawauchi and Jones, {David T.W.} and Charles Spruck and Taylor, {Michael D.} and Cho, {Yoon Jae} and Pfister, {Stefan M.} and Marcel Kool and Andrey Korshunov and Swartling, {Fredrik J.} and Olle Sangfelt",
note = "Funding Information: This work was supported by research grants from the Swedish Childhood Cancer Foundation (FJS, OS, ASR), the Swedish Cancer Society (FJS, OS), the Swedish Research Council (FJS, OS), the European Research Council under Horizon 2020 (Project No. 640275, Medulloblastoma - ERC-2014-STG) (FJS), the Ragnar S{\"o}derberg Foundation (FJS), the Swedish Society of Medicine (FJS), the {\AA}ke Wiberg Foundation (FJS), Science for Life Laboratory (FJS, OS), {\AA}ke Olssons Stiftelse (OS), Radiumhemmets Forskningsfonder (OS, ASR), Karolinska Institute Foundations (OS, AB), and Worldwide Cancer Research (FJS). We thank Bert Vogelstein (Johns Hopkins University) for providing HCT116 FBXW7 KO/WT cells and Peter Koopman (Institute for Molecular Bioscience, University of Queensland) for providing pcDNA3.1 HA-SOX9 plasmid. We also acknowledge technical support from the National Genomics Infrastructure (NGI)/Uppsala Genome Center and UPPMAX for providing assistance in massive parallel sequencing and computational infrastructure. Work performed at NGI/Uppsala Genome Center has been funded by RFI/VR and the Science for Life Laboratory, Sweden. We further acknowledge support with imaging from the BioVis facility at the Science for Life Laboratory, Uppsala University, Sweden, and Janne Lehti{\"o} for proteomic analysis at the Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden. Publisher Copyright: {\textcopyright} 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license",
year = "2016",
month = oct,
day = "17",
doi = "10.15252/embj.201693889",
language = "English (US)",
volume = "35",
pages = "2192--2212",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "20",
}