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

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 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. Mol Cancer Ther; 9(9); 2568-81. ©2010 AACR.

The Simultaneous Effect of Valproic Acid and Gamma Radiation on Telomerase Activity and Bax and Bcl-2 Protein Levels in MCF-7 Breast Cancer Cell Line

“…It could be due to an inhibitory effect of HDACI on telomerase holoenzyme and consequent cell death (26,27).…”

Human telomerase inhibitors from microbial source

“…Among the numerous transcription factors regulating hTERT expression, increased levels of c-MYC act as a transcription activator whereas Smad3 and Mad1 proteins act as repressors of hTERT gene expression. Trichostatin-A usually elicit Smad3, Mad1 gene expression and this in turn leads to the down regulation of hTERT (Rahman et al 2010). At present it is regarded as an effective anti proliferative agent and clinical trials are on the way.…”

Epigenetics, Nervous System Tumors, and Cancer Stem Cells

“…The organization of telomeric chromatin influences telomere maintenance, and telomere dysfunction affects telomeric and subtelomeric chromatin formation and activates alternative telomere maintenance mechanisms [162]. Further, treatment of nervous system tumor cells with HDAC inhibitors has been shown to have antiproliferative and proapoptotic effects, mediated by alterations in chromatin at the telomerase reverse transcriptase (TERT) promoter [163]. Moreover, telomeres are transcribed into ncRNAs, telomere repeat-containing RNA (TERRA), that may have roles in modulating telomeric heterochromatin formation, the accessibility of telomeres to DNA repair mechanisms, and the activity of telomerase [164].…”