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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)3172-3182
Number of pages11
JournalOncogene
Volume33
Issue number24
DOIs
Publication statusPublished - 2014 Jun 12

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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

Cite this

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. In: Oncogene. 2014 ; Vol. 33, No. 24. pp. 3172-3182.
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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, vol. 33, no. 24, pp. 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.

In: Oncogene, Vol. 33, No. 24, 12.06.2014, p. 3172-3182.

Research output: Contribution to journalArticle

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

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AU - Wang, W. L.

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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.

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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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