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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Glycogen synthase kinase 3 beta (GSK3β) is inactivated in epithelial cancers, inhibiting tumor migration.
• Slug, a zinc-finger transcriptional repressor, promotes epithelial-mesenchymal transition (EMT) by repressing E-cadherin.
• Understanding the regulation of Slug is crucial for targeting cancer metastasis.

Purpose of the Study:

• To investigate the relationship between GSK3β activity and Slug expression in non-small cell lung cancer.
• To elucidate the mechanism by which GSK3β regulates Slug protein stability.
• To identify novel pathways involved in lung cancer metastasis.

Main Methods:

• Analysis of GSK3β-pSer9 levels and Slug expression in non-small cell lung cancer.
• Investigation of GSK3β-mediated phosphorylation of Slug.
• Proteomic analysis to identify Slug-interacting proteins, including CHIP.
• CHIP knockdown and ubiquitylation assays.
• Assessment of Slug mutant stability and its effect on E-cadherin and cell migration.

Main Results:

• GSK3β-pSer9 levels correlate with Slug expression in lung cancer.
• GSK3β-mediated phosphorylation promotes Slug protein degradation.
• Carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with and ubiquitinates wild-type Slug (wtSlug).
• CHIP knockdown stabilizes wtSlug, reducing its ubiquitylation and degradation.
• Nonphosphorylatable Slug mutant (Slug-4SA) is resistant to CHIP-mediated degradation.
• Accumulation of nondegradable Slug enhances E-cadherin repression, promoting migration, invasion, and metastasis.

Conclusions:

• A novel GSK3β-CHIP-Slug signaling pathway regulates Slug stability and promotes lung cancer metastasis.
• GSK3β inactivation and subsequent Slug accumulation contribute to cancer cell migration, invasion, and metastasis.
• Targeting this pathway may offer therapeutic strategies for inhibiting lung cancer progression.