Glioma Stem Cells Are Sensitized to BCL-2 Family Inhibition by Compromising Histone Deacetylases
Aran Merati1, Spandana Kotian1, Alexus Acton1
1Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Abstract:
Glioblastoma (GBM) remains an incurable disease with an extremely high five-year recurrence rate. We studied apoptosis in glioma stem cells (GSCs) in response to HDAC inhibition (HDACi) combined with MEK1/2 inhibition (MEKi) or BCL-2 family inhibitors. MEKi effectively combined with HDACi to suppress growth, induce cell cycle defects, and apoptosis, as well as to rescue the expression of the pro-apoptotic BH3-only proteins BIM and BMF. A RNAseq analysis of GSCs revealed that HDACi repressed the pro-survival BCL-2 family genes MCL1 and BCL-XL. We therefore replaced MEKi with BCL-2 family inhibitors and observed enhanced apoptosis. Conversely, a ligand for the cancer stem cell receptor CD44 led to reductions in BMF, BIM, and apoptosis. Our data strongly support further testing of HDACi in combination with MEKi or BCL-2 family inhibitors in glioma.
Insights
This study explores combining HDAC inhibitors with MEK inhibitors or BCL-2 inhibitors to treat glioblastoma stem cells. These combinations show promise in inducing apoptosis and suppressing cancer growth.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Stem Cell Research
Background:
- Glioblastoma (GBM) is a highly aggressive brain tumor with a poor prognosis and high recurrence rate.
- Glioma stem cells (GSCs) are implicated in GBM's resistance to therapy and recurrence.
- Targeting apoptosis pathways is a critical strategy for overcoming GBM treatment resistance.
Purpose of the Study:
- To investigate the efficacy of combining histone deacetylase inhibitors (HDACi) with MEK1/2 inhibitors (MEKi) or BCL-2 family inhibitors in GSCs.
- To elucidate the molecular mechanisms underlying the response of GSCs to these combination therapies.
- To identify potential therapeutic strategies for improving GBM treatment outcomes.
Main Methods:
- Treatment of GSCs with HDACi, MEKi, and/or BCL-2 family inhibitors.
- Assessment of cell viability, cell cycle progression, and apoptosis induction.
- RNA sequencing (RNAseq) analysis to profile gene expression changes.
- Investigation of BH3-only proteins (BIM, BMF) and BCL-2 family gene expression (MCL1, BCL-XL).
Main Results:
- HDACi combined with MEKi suppressed GSC growth, induced cell cycle defects, and promoted apoptosis.
- This combination therapy restored the expression of pro-apoptotic proteins BIM and BMF.
- HDACi downregulated pro-survival BCL-2 family genes MCL1 and BCL-XL, leading to enhanced apoptosis when MEKi was replaced with BCL-2 inhibitors.
- CD44 ligand treatment reduced BIM, BMF, and apoptosis, highlighting a counteracting mechanism.
Conclusions:
- Combination therapy of HDACi with MEKi or BCL-2 family inhibitors demonstrates significant potential for inducing apoptosis in GSCs.
- Targeting specific apoptosis regulators and survival pathways offers a promising avenue for novel GBM therapies.
- Further clinical investigation of HDACi combined with MEKi or BCL-2 inhibitors is warranted for glioma treatment.
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