hTERT in cancer chemotherapy: A novel target of histone deacetylase inhibitors

Chromatin structure plays an important role in the regulation of gene transcription. Chromatin structure can be modified by various post-translational modifications, including histone acetylation, phosphorylation, methylation and ribosylation. Among those modifications, histone acetylation/deacetylation is the most important mechanism for regulating transcription and is regulated by a group of enzymes known as histone acetyltransferases/histone deacetylases (HDACs). Recently, HDAC inhibitors have been shown to be a novel and promising new class of anti-cancer agent that can regulate the transcription of genes by disrupting the balance of acetylation/deacetylation in particular regions of chromatin. A number of HDAC inhibitors are currently in phase I and II clinical trials against a variety of cancers. Although some promising candidates have been identified (e.g., p21^WAF1 and c-Myc), the precise molecular targets remain uncertain. In this article, we focus on one of the DNA polymerases, telomerase, as a new candidate molecular target for HDAC inhibitors. Telomerase is composed primarily of the catalytic subunit (hTERT) and the RNA template (hTERC), and its activity correlates with levels of hTERT mRNA. hTERT expression is apparently governed by complicated regulatory pathways. Based on recent studies, the hTERT gene is likely to be targeted by histone acetylation/deacetylation.