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.

SRY-Box Containing Gene 4 Promotes Liver Steatosis by Upregulation of SREBP-1c

“…However, whether other members of the Sox family are involved in maintaining hepatic lipid homeostasis is worth studying. Especially, recent studies demonstrated that ubiquitination-mediated protein stability and degradation have an important role for the aberrant expression of SOX9 in human malignancy (40,41). Besides, a methylation-phosphorylation switch controls SOX2 protein stability in embryonic stem cell differentiation (42).…”

SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage

“…Failure of GSK3β to phosphorylate SOX9 prevents the binding of FBW7 to the consensus CPD site on SOX9, located within the K2 transactivation domain, and prevents the degradation of SOX9 both under normal conditions and after DNA damage. Indeed, Sangfelt and colleagues also observed that SOX9 protein is stabilized by FBW7 repression in meduloblastoma under normal conditions ( 69 ). In our study, loss of SOX9 after DNA damage participates in UV damage-induced cell death, because overexpressed SOX9 increases cell survival even after genotoxic stress (Figure 7 ).…”

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…However, enhance phosphorylation of AKT via PI3K or mTOR to restrain GSK3 in MBM, which lead to SOX9 degradation is reduced due to the facts that FBW7 degrades SOX9 under the guidance of GSK3. The loss of FBW7 function increases SOX9 protein levels, increasing the malignancy of cancer and resistance to cisplatin [35]. As a major oncoprotein inhibitor, once FBW7 is deleted or mutated, it can cause tumors to occur directly [36,37].…”

“…So targeted inhibition of the PI3K pathway has a bright therapeutic potential in MBM. Moreover, experiments show that combination of PI3K inhibitor, mTOR inhibitor and cisplatin can achieve better therapeutic effect [35], and how well LY3023414 works in recurrent MBM is being tested in an ongoing clinical trial (NCT03213678, Table 2).…”