Apoptotic pathways activated by histone deacetylase inhibitors: implications for the drug-resistant phenotype.

Histones are abundant proteins that coordinate the organization of eukaryotic nucleosomes. Post-translational modifications of histones-acetylation, phosphorylation and methylation-locally modulate the higher order nucleosome structure. Acetylation and deacetylation of histones occur at their N-terminal tails in a dynamic fashion and influence DNA accessibility to factors regulating replication, repair and transcription. Acetylation, catalyzed by histone acetyltransferases (HATs) on the epsilon-NH(2) group of lysine residues, neutralizes the positive charge and thereby triggers transcriptional activation. Deacetylation, catalyzed by histone deacetylases (HDACs) on the same lysine residues, unmasks the charge and triggers transcriptional repression. Inhibition of HDACs has thus a broad effect on chromatin architecture, and possibly on protein function, and multiple effects on cell growth. HDAC inhibitors (HDIs) are promising as single anti-cancer agents and in combination therapies. Understanding of the molecular basis for HDIs action is needed to better design the clinical antitumor treatments. The apoptotic pathways induced by HDIs are emerging and we provide an overview of the recent findings that regard apoptotic key elements. We also propose that transformed cells discern the widespread effect of HDIs on chromatin architecture as a genotoxic insult to respond to through induction of apoptosis.