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 language | English |
|---|---|
| Pages (from-to) | 3172-3182 |
| Number of pages | 11 |
| Journal | Oncogene |
| Volume | 33 |
| Issue number | 24 |
| DOIs | |
| Publication status | Published - 2014 Jun 12 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Genetics
- Cancer Research
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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 journal › Article
TY - JOUR
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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U2 - 10.1038/onc.2013.279
DO - 10.1038/onc.2013.279
M3 - Article
VL - 33
SP - 3172
EP - 3182
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 24
ER -