Histone Deacetylase Inhibition Attenuates Cell Growth with Associated Telomerase Inhibition in High-Grade Childhood Brain Tumor Cells

Rahman, R.; Osteso-Ibanez, T.; Hirst, R. A.; Levesley, J.; Kilday, J.-P.; Quinn, S.; Peet, A.; O'Callaghan, C.; Coyle, B.; Grundy, R. G.

Abstract

Aberrant epigenetic regulation of gene expression contributes to tumor initiation and progression. Studies from a plethora of hematologic and solid tumors support the use of histone deacetylase inhibitors (HDACi) as potent anticancer agents. However, the mechanism of HDACi action with respect to the temporal order of induced cellular events is unclear. The present study investigates the anticancer effects of the HDACi trichostatin A in high-grade childhood brain tumor cells. Acute exposure to trichostatin A resulted in marked inhibition of cell proliferation, an increase in the proportion of G2-M cells, activation of H2A.X, and subsequent induction of apoptosis in the majority of cell lines. These phenotypic effects were associated with abrogation of telomerase activity and human telomerase reverse transcriptase downregulation in the majority of cell lines. In contrast, no cytotoxicity was observed in primary ependymal cells with respect to cilia function. Thus, inhibition of histone deacetylases leads to antiproliferative and proapoptotic effects in childhood brain tumor cells, likely to involve altered chromatin regulation at the human telomerase reverse transcriptase promoter.

Citation

Rahman, R., Osteso-Ibanez, T., Hirst, R. A., Levesley, J., Kilday, J.-P., Quinn, S., Peet, A., O'Callaghan, C., Coyle, B., & Grundy, R. G. (2010). Histone Deacetylase Inhibition Attenuates Cell Growth with Associated Telomerase Inhibition in High-Grade Childhood Brain Tumor Cells. Molecular Cancer Therapeutics, 9(9), 2568-2581. https://doi.org/10.1158/1535-7163.mct-10-0272

• Journal Article Type: Article
• Acceptance Date: Jun 27, 2010
• Online Publication Date: Jul 19, 2010
• Publication Date: Sep 1, 2010
• Deposit Date: Dec 5, 2018
• Journal: Molecular Cancer Therapeutics
• Print ISSN: 1535-7163
• Electronic ISSN: 1538-8514
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 9
• Pages: 2568-2581
• DOI: https://doi.org/10.1158/1535-7163.mct-10-0272
• Public URL: https://nottingham-repository.worktribe.com/output/1370656
• Publisher URL: https://mct.aacrjournals.org/content/9/9/2568