FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma
2016 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 35, no 20, 2192-2212 p.Article in journal (Refereed) Published
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 SCFFBW7 alpha. 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.
Place, publisher, year, edition, pages
2016. Vol. 35, no 20, 2192-2212 p.
FBW7, SOX9, Medulloblastoma, FBXW7, ubiquitin, migration, metastasis, drug resistance
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-274626DOI: 10.15252/embj.201693889ISI: 000385708000004OAI: oai:DiVA.org:uu-274626DiVA: diva2:897102
FunderSwedish Childhood Cancer FoundationSwedish Cancer SocietySwedish Research CouncilEU, European Research Council, 640275Ragnar Söderbergs stiftelseSwedish Society of MedicineÅke Wiberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceThe Karolinska Institutet's Research Foundation
Aldwin Suryo Rahmanto and Vasil Savov contributed equally to this work as first authors
Andrä Brunner, Sara Bolin and Holger Weishaupt contributed equally to this work as second authors
Fredrik J Swartling and Olle Sangfelt contributed equally to this work as corresponding authors2016-01-242016-01-242016-11-21Bibliographically approved