Histone deacetylase inhibition attenuates cell growth with associated telomerase inhibition in high-grade childhood brain tumor cells.

Ruman Rahman, Teresa Osteso-Ibanez, Robert A Hirst, Jane Levesley, John-Paul Kilday, Siobhan Quinn, Andrew Peet, Chris O'Callaghan, Beth Coyle, Richard G Grundy

Children's Brain Tumor Research Centre, Medical School, University of Nottingham, Nottingham, United Kingdom.

Molecular cancer therapeutics 2010 Sep

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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 G(2)-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

Ruman Rahman, Teresa Osteso-Ibanez, Robert A Hirst, Jane Levesley, John-Paul Kilday, Siobhan Quinn, Andrew Peet, Chris O'Callaghan, Beth Coyle, Richard G Grundy. Histone deacetylase inhibition attenuates cell growth with associated telomerase inhibition in high-grade childhood brain tumor cells. Molecular cancer therapeutics. 2010 Sep;9(9):2568-81