FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma.
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 SCFFBW7αFailure 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.
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Aldwin
0000-0002-4593-286X
A
Suryo Rahmanto
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Vasil
V
Savov
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Andrä
A
Brunner
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Sara
S
Bolin
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Holger
H
Weishaupt
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
Alena
A
Malyukova
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Gabriela
G
Rosén
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Matko
M
Čančer
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Sonja
S
Hutter
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Anders
A
Sundström
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Daisuke
D
Kawauchi
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
David Tw
DT
Jones
Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA.
Charles
C
Spruck
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
Michael D
MD
Taylor
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Yoon-Jae
YJ
Cho
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Pediatric Hematology and Oncology, University Hospital, Heidelberg, Germany.
Stefan M
SM
Pfister
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Marcel
M
Kool
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neuropathology, University Hospital, Heidelberg, Germany.
Andrey
A
Korshunov
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.
Fredrik J
0000-0002-8460-4367
FJ
Swartling
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden fredrik.swartling@igp.uu.se olle.sangfelt@ki.se.
Olle
0000-0002-0316-0195
O
Sangfelt
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001549:Benzamides; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002867:Chromones / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D000814:Aniline Compounds; D001549:Benzamides; D018797:Cell Cycle Proteins; D002867:Chromones; D002945:Cisplatin; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D011758:Pyrroles; D055758:SOX9 Transcription Factor; D058570:TOR Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; C000595972:AZD8186; C513273:FBXW7 protein, human; C527932:SOX9 protein, human; C585537:vistusertib; C546842:MTOR protein, human; C575618:capivasertib
FBW7; SOX9; cisplatin; medulloblastoma; metastasis