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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.

Authors

T. Osteso-Ibanez

R. A. Hirst

J. Levesley

J.-P. Kilday

S. Quinn

A. Peet

C. O'Callaghan

BETH COYLE BETH.COYLE@NOTTINGHAM.AC.UK
Associate Professor

R. G. Grundy



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.

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