Targeting class I histone deacetylases in cancer therapy

Class I histone deacetylases (HDACs) are often overexpressed in cancer, and their inhibition typically leads cancer cells, but not normal cells, to apoptosis. Hence, the field of cancer therapy has experienced a continued surge in the development of HDAC inhibitors.

Class I comprises of HDAC1, 2, 3 and 8. HDAC1, 2 and 3 are active as subunits of multiprotein complexes while an HDAC8 complex has not been identified. Besides being a major contributor to poor prognosis in childhood neuroblastoma, little is known of HDAC8 functions and substrates. The targeting and activities of HDAC1 - 3 are modulated by post-translational modifications and association with numerous proteins. The composition of the various HDAC complexes is cell type dependent and fluctuates with intra- and intercellular stimuli. These HDAC complexes play roles at multiple levels in gene expression and genome stability. The application of isoform-specific HDAC inhibitors has met with varying success in clinical trials.

To elucidate the mechanism and cellular impact of HDAC inhibitors, we need to identify the spectrum of class I HDAC complexes and their functions. In the cases of HDAC1 - 3, selectivity of HDAC inhibitors should be directed against relevant complexes. HDAC8 active site unique features facilitate the design of selective inhibitors.