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Inhibition of BET bromodomain targets genetically diverse glioblastoma
Zhixiang Cheng1, Yuanying Gong, Yufang Ma
1Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Purpose:
Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples.
Experimental Design:
The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors.
Results:
We showed that JQ1 induced marked G1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21(CIP1/WAF1), hTERT, Bcl-2, and Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21(CIP1/WAF1) attenuated JQ1-induced cell-cycle arrest. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors.
Conclusion:
Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors.
Insights
A novel BET bromodomain inhibitor, JQ1, shows therapeutic potential against glioblastoma. JQ1 effectively inhibits glioblastoma cell growth and tumor progression by inducing cell-cycle arrest and apoptosis.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Glioblastoma is a highly aggressive brain tumor with limited treatment options.
- Bromodomain and extraterminal domain (BET) proteins are epigenetic regulators and emerging therapeutic targets.
- BET inhibitors have shown promise in other cancers, but their efficacy in glioblastoma is less understood.
Purpose of the Study:
- To evaluate the therapeutic potential of the novel BET bromodomain inhibitor JQ1 in glioblastoma.
- To assess JQ1's effects on genetically diverse glioblastoma samples.
- To investigate the mechanisms underlying JQ1's antineoplastic activity in glioblastoma.
Main Methods:
- Ex vivo culture of primary glioblastoma xenograft lines and surgical specimens.
- In vivo efficacy assessment in orthotopic glioblastoma tumor models.
- Analysis of cell-cycle arrest, apoptosis, and gene expression changes following JQ1 treatment.
Main Results:
- JQ1 induced significant G1 cell-cycle arrest and apoptosis in glioblastoma cells.
- JQ1 altered the expression of key glioblastoma genes including c-Myc, p21(CIP1/WAF1), hTERT, Bcl-2, and Bcl-xL.
- JQ1 demonstrated significant repression of orthotopic glioblastoma tumor growth, and efficacy was not compromised by common resistance mutations.
Conclusions:
- JQ1 exhibits potent antineoplastic effects against glioblastoma.
- The findings suggest broad therapeutic applicability of BET bromodomain inhibitors for diverse glioblastoma tumors.
- JQ1 represents a promising therapeutic strategy for glioblastoma treatment.
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