A Mechanistic Approach to Anticancer Therapy: Targeting the Cell Cycle with Histone Deacetylase Inhibitors

C.   N.   Mork; D.   V.   Faller; R.   A.   Spanjaard

Abstract

The activity of genes encoded by the highly-condensed DNA in cellular nuclei must be precisely regulated. Regulation of the accessibility of gene promoters to transcription complexes is one level of gene regulation and is influenced by histone tail modifications such as acetylation, methylation, and phosphorylation. Acetylation is a reversible modification catalyzed by histone acetyl transferase (HAT) and histone deacetyltransferase (HDAC) enzymes. Histone deacetylation is associated with transcriptional repression of genes, as the removal of acetyl groups from lysine residues allows for tighter electrostatic interactions between DNA and histones, limiting accessibility of the DNA for transcription. Inhibition of HDAC activity permits histones to remain in an acetylated state, and through the resulting alterations in gene regulation, inhibits cell cycle progression, inhibits differentiation, and in some cases induces apoptosis. Inhibition of proliferation by HDAC inhibitors is characterized by arrest at the G1 or G2/M phases of the cell cycle. Many types of tumor cells then undergo programmed cell death. Exposure to HDAC inhibitors may also allow reactivation of tumor suppressor genes which had been silenced by hypoacetylation during tumorigenesis. HDAC inhibitors from a number of chemical classes have shown promise as anti-cancer agents in animal studies and early clinical trials. The development of HDAC inhibitors which specifically target HDAC isozymes, and more detailed understanding of their anti-neoplastic actions, heralds a new epigenetic antitumor therapeutic strategy.

Keywords: hdac, hat, histone acetyltransferase, butyrate, hydroxamic acid, gene transcription, valproic acid, saha