Inhibition of telomerase activity and human telomerase reverse transcriptase gene expression by histone deacetylase inhibitor in human brain cancer cells

Mutat Res. 2007 Dec 1;625(1-2):134-44. doi: 10.1016/j.mrfmmm.2007.06.005. Epub 2007 Jun 26.

Abstract

The aim of the present study is to investigate the effect of histone deacetylase inhibitor, trichostatin A (TSA) on the cell growth, apoptosis, genomic DNA damage and the expression of telomerase and associated factors in human normal and brain cancer cells. Here, human normal un-transformed fibroblasts (MRC-5), human normal hTERT-immortalised fibroblasts (hTERT-BJ1) and human brain cancer cell lines (glioblastoma cell line, A-172 and medulloblastoma cell line, ONS-76) were treated with 0.5-3.0microM TSA for 24h. Exposure to TSA resulted in apoptosis in a dose-dependent manner in the brain cancer cells. Glioblastoma cell line (A-172) displayed higher sensitivity to TSA-induced cell killing effect and apoptosis than the medulloblastoma cell line (ONS-76). The brain cancer cell lines and hTERT-BJ1 cell line displayed significant inhibition in telomerase activity and hTERT mRNA level after 2microM TSA treatment. Elevated expressions of p53 and p21 with a decrease in cyclin-D level supported the observation on cell cycle arrest following TSA treatment. Upregulation of Bax and cytochrome c correlated with the apoptotic events in TSA-treated cells. This study suggests that telomerase and hTERT might be the primary targets of TSA which may have the potential to be used as a telomerase inhibitor in cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • DNA Repair
  • DNA Replication / drug effects
  • Gene Expression / drug effects
  • Genomic Instability / drug effects
  • Genomic Instability / physiology
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology
  • In Situ Hybridization, Fluorescence
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Telomerase / antagonists & inhibitors*
  • Telomerase / genetics

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • RNA, Messenger
  • RNA, Neoplasm
  • trichostatin A
  • Telomerase