GSK3β controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of slug

S. H. Kao, W. L. Wang, C. Y. Chen, Y. L. Chang, Y. Y. Wu, Y. T. Wang, S. P. Wang, A. I. Nesvizhskii, Y. J. Chen, Tse-Ming Hong, P. C. Yang

研究成果: Article

64 引文 (Scopus)

摘要

Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug in non-small cell lung cancer. GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.

原文English
頁(從 - 到)3172-3182
頁數11
期刊Oncogene
33
發行號24
DOIs
出版狀態Published - 2014 六月 12

指紋

HSC70 Heat-Shock Proteins
Gastropoda
Epithelial-Mesenchymal Transition
Proteolysis
Neoplasm Metastasis
Neoplasms
Cadherins
Glycogen Synthase Kinase 3 beta
Ubiquitination
Zinc Fingers
Non-Small Cell Lung Carcinoma
Proteomics
Cell Movement
Lung Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

引用此文

Kao, S. H., Wang, W. L., Chen, C. Y., Chang, Y. L., Wu, Y. Y., Wang, Y. T., ... Yang, P. C. (2014). GSK3β controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of slug. Oncogene, 33(24), 3172-3182. https://doi.org/10.1038/onc.2013.279
Kao, S. H. ; Wang, W. L. ; Chen, C. Y. ; Chang, Y. L. ; Wu, Y. Y. ; Wang, Y. T. ; Wang, S. P. ; Nesvizhskii, A. I. ; Chen, Y. J. ; Hong, Tse-Ming ; Yang, P. C. / GSK3β controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of slug. 於: Oncogene. 2014 ; 卷 33, 編號 24. 頁 3172-3182.
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abstract = "Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug in non-small cell lung cancer. GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.",
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Kao, SH, Wang, WL, Chen, CY, Chang, YL, Wu, YY, Wang, YT, Wang, SP, Nesvizhskii, AI, Chen, YJ, Hong, T-M & Yang, PC 2014, 'GSK3β controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of slug', Oncogene, 卷 33, 編號 24, 頁 3172-3182. https://doi.org/10.1038/onc.2013.279

GSK3β controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of slug. / Kao, S. H.; Wang, W. L.; Chen, C. Y.; Chang, Y. L.; Wu, Y. Y.; Wang, Y. T.; Wang, S. P.; Nesvizhskii, A. I.; Chen, Y. J.; Hong, Tse-Ming; Yang, P. C.

於: Oncogene, 卷 33, 編號 24, 12.06.2014, p. 3172-3182.

研究成果: Article

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T1 - GSK3β controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of slug

AU - Kao, S. H.

AU - Wang, W. L.

AU - Chen, C. Y.

AU - Chang, Y. L.

AU - Wu, Y. Y.

AU - Wang, Y. T.

AU - Wang, S. P.

AU - Nesvizhskii, A. I.

AU - Chen, Y. J.

AU - Hong, Tse-Ming

AU - Yang, P. C.

PY - 2014/6/12

Y1 - 2014/6/12

N2 - Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug in non-small cell lung cancer. GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.

AB - Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug in non-small cell lung cancer. GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.

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