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

Hong, Xuehui; Liu, Wenyu; Song, Ran; Shah, Jamie J.; Feng, Xing; Tsang, Chi Kwan; Morgan, Katherine M.; Bunting, Samuel F.; Inuzuka, Hiroyuki; Zheng, Xingnan; Shen, Zhiyuan; Sabaawy, Hatem E.; Liu, Lian Xin; Pine, Sharon R.

doi:10.1093/nar/gkw748

Cited by 48 publications

(46 citation statements)

References 83 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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Obesity is usually associated with an increased risk of nonalcoholic fatty liver disease that is characterized by accumulation of excessive triglyceride (TG) in hepatocytes. However, the factors involved in the obesity-induced hepatosteatosis are poorly defined. Here, we report that SRY-box containing gene 4 (), a transcription factor that regulates cell proliferation and differentiation, plays an important role in hepatic TG metabolism. expression levels are markedly upregulated in livers of obese rodents and humans. Adenovirus-medicated overexpression of in the livers of lean mice promotes liver steatosis, whereas liver-specific knockdown of ameliorates TG accumulation and improves insulin resistance in obese mice. At the molecular level, we show that could directly control the transcription of gene through binding to its proximal promoter region. Thus, we have identified as an important component of hepatic TG metabolism.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…Small-molecule inhibitors of the PI3K/mTOR pathway can be used to stimulate GSK3/FBW7a-mediated SOX9 turnover and may provide a novel strategy to target SOX9-driven medulloblastoma. (Hong et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma

et al. 2016

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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.

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“…Western blotting was performed as previously described (28). Xenograft tumor samples were snap-frozen in liquid nitrogen and stored at −80°C.…”

Section: Methodsmentioning

confidence: 99%

Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

Morgan

Fischer

Lee

et al. 2017

Molecular Cancer Therapeutics

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Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor (GSI), and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14 human NSCLC cell lines. There was significantly greater synergy between BMS-906024 and paclitaxel than BMS-906024 and cisplatin (mean CI value = 0.54 and 0.85, respectively, P = 0.01). On an extended panel of 31 NSCLC cell lines, 25 of which were adenocarcinoma, the synergy between BMS-906024 and paclitaxel was significantly greater in KRAS- and BRAF-wildtype than KRAS- or BRAF-mutant cells (mean CI = 0.43 vs. 0.90, respectively; P = 0.003). Paclitaxel-induced Notch1 activation was associated with synergy between BMS-906024 and paclitaxel in the KRAS- or BRAF-mutant group. Knockdown of mutant KRAS increased the synergy between BMS-906024 and paclitaxel in heterozygous KRAS-mutant cell lines. Among KRAS- or BRAF-mutant NSCLC, there was a significant correlation between synergy and mutant or null TP53 status, as well as between synergy and a low H2O2 pathway signature. Exogenous overexpression of activated Notch1 or Notch3 had no effect on the enhanced sensitivity of NSCLC to paclitaxel by BMS-906024. In vivo studies with cell line- and patient-derived lung adenocarcinoma xenografts confirmed enhanced antitumor activity for BMS-906024 plus paclitaxel versus either drug alone via decreased cell proliferation and increased apoptosis. These results show that BMS-906024 sensitizes NSCLC to paclitaxel, and that wildtype KRAS and BRAF status may predict better patient response to the combination therapy.

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

Cited by 48 publications

References 83 publications

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

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

FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma

Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma

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