Suberoylanilide hydroxamic acid represses glioma stem-like cells
Che-Chia Hsu1,2, Wen-Chang Chang1, Tsung-I Hsu2
1Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, 11031, Taiwan.
Background:
Glioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties.
Methods:
Human GBM cell lines were plated in serum-free suspension cultures allowed for sphere forming and CSC enrichment. Subsequently, upon SAHA treatment, the stemness markers, cell proliferation, and viability of GSCs as well as cellular apoptosis and senescence were examined in order to clarify whether inhibition of GSCs occurs.
Results:
We demonstrated that SAHA attenuated cell proliferation and diminished the expression stemness-related markers (CD133 and Bmi1) in GSCs. Furthermore, at high concentrations (more than 5 μM), SAHA triggered apoptosis of GSCs accompanied by increases in both activation of caspase 8- and caspase 9-mediated pathways. Interestingly, we found that a lower dose of SAHA (1 μM and 2.5 μM) inhibited GSCs via cell cycle arrest and induced premature senescence through p53 up-regulation and p38 activation.
Conclusion:
SAHA induces apoptosis and functions as a potent modulator of senescence via the p38-p53 pathway in GSCs. Our results provide a perspective on targeting GSCs via SAHA treatment, and suggest that SAHA could be used as a potent agent to overcome drug resistance in GBM patients.
Insights
Suberoylanilide hydroxamic acid (SAHA) effectively targets glioma stem-like cells (GSCs) by inducing apoptosis and senescence. This histone deacetylase inhibitor offers a promising strategy to overcome glioblastoma multiforme (GBM) treatment resistance.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Epigenetics
Background:
- Glioblastoma multiforme (GBM) exhibits high treatment resistance, often attributed to glioma stem-like cells (GSCs).
- Histone deacetylase (HDAC) activity is implicated in cancer stem-like cell (CSC) properties and abundance.
- Investigating novel therapeutic strategies to target GSCs is crucial for improving GBM patient outcomes.
Purpose of the Study:
- To investigate the effects of suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, on GSCs.
- To elucidate the mechanism by which SAHA modulates GSC stemness and viability.
- To assess SAHA's potential in overcoming therapeutic resistance in GBM.
Main Methods:
- Human GBM cell lines were cultured in serum-free conditions to enrich for GSCs.
- GSCs were treated with SAHA, and subsequent analyses included stemness markers, proliferation, viability, apoptosis, and senescence.
- Key molecular pathways, including caspase activation, p53, and p38, were examined.
Main Results:
- SAHA treatment significantly attenuated GSC proliferation and reduced expression of stemness markers (CD133, Bmi1).
- High SAHA concentrations induced GSC apoptosis via caspase 8 and 9 activation.
- Lower SAHA doses triggered cell cycle arrest and premature senescence, involving p53 up-regulation and p38 activation.
Conclusions:
- SAHA effectively induces apoptosis and modulates senescence in GSCs through the p38-p53 pathway.
- SAHA demonstrates potential as a therapeutic agent for targeting GSCs in GBM.
- These findings suggest SAHA could be a valuable strategy to overcome drug resistance in glioblastoma patients.
