Targeting class I histone deacetylases in cancer therapy.
BACKGROUND
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.


METHODS
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.


CONCLUSIONS
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.
University of Manitoba, Manitoba Institute of Child Health, 715 McDermot Avenue, Room 600A, Winnipeg, Manitoba, R3E 3P4, Canada.
Geneviève P
GP
Delcuve
Dilshad H
DH
Khan
James R
JR
Davie
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases