BIS-mediated STAT3 stabilization regulates glioblastoma stem cell-like phenotypes

Area of Science:

• Oncology
• Cancer Biology
• Molecular Cell Biology

Background:

• Glioblastoma stem cells (GSCs) drive tumor growth and therapy resistance.
• Bcl-2-interacting cell death suppressor (BIS), also known as BAG3, is an anti-apoptotic protein overexpressed in glioblastoma.
• The role of BIS in GSC maintenance and glioblastoma progression is not fully understood.

Purpose of the Study:

• To investigate the role of BIS in glioblastoma stem-like cell populations.
• To determine the molecular mechanisms by which BIS influences GSC properties and STAT3 signaling.
• To evaluate BIS as a potential therapeutic target in glioblastoma.

Main Methods:

• Examined BIS expression in glioblastoma cell lines (A172, U87-MG) under sphere-forming conditions.
• Assessed the impact of BIS depletion on GSC sphere formation, SOX-2, and STAT3 expression.
• Utilized immunoprecipitation and confocal microscopy to study BIS-STAT3 interaction.
• Investigated the effect of BIS depletion on STAT3 ubiquitination and epithelial-to-mesenchymal transition (EMT)-related genes.

Main Results:

• BIS mRNA and protein levels were significantly upregulated in GSC-like spheres compared to standard cultures.
• BIS depletion reduced sphere-forming activity, SOX-2 expression, and nuclear phosphorylated STAT3 levels.
• BIS physically interacts with STAT3, and BIS depletion increases STAT3 ubiquitination, indicating BIS stabilizes STAT3.
• BIS depletion decreased SNAIL and MMP-2 expression while increasing E-cadherin, suggesting inhibition of EMT.

Conclusions:

• High BIS expression promotes stem-cell-like properties in glioblastoma cells, likely through STAT3 stabilization.
• BIS plays a critical role in maintaining GSC characteristics and potentially contributes to therapy resistance.
• BIS represents a promising therapeutic target for glioblastoma treatment.