Histone deacetylases (HDACs) are enzymes that catalyze a chemical modification (deacetylation) of histones, proteins that form complexes with DNA. Histone acetylation and deacetylation is known to be involved in controlling the transcriptional activity of genes. Two Ithaca College undergraduates, Keris Krennhrubec and Mark Hedglin, designed and synthesized molecules that inhibit one HDAC family member, HDAC8, selectively among the ten human HDACs by exploiting a unique structural feature of HDAC8.
In collaboration with researchers at the Gladstone Institute for Virology and Immunology, human cells were treated with HDAC8 inhibitors; results showed that HDAC8 does not deacetylate histones, as the family name suggests. Rather, HDAC8 deacetylates tubulin and other non-histone proteins not yet identified.
This result adds to a small number of previous reports showing that the HDAC family has functions outside the traditional one of controlling transcription. Identification of the targets of HDAC8 should expose new biological processes regulated by reversible acetylation.
HDAC8 also has links to acute mylogenous leukemia (AML), a disease that is currently treated with intensive chemotherapy and bone marrow transplants. AML is characterized by a genetic lesion that creates an unnatural fusion protein called Inv1. Inv1 forms a genetic repressor complex with HDAC8, and it may be that the molecular etiology of AML involves aberrant HDAC8 function. If so, HDAC8 inhibitors could be useful to treat AML.
Researchers at the Gladstone Institutes and at the Metastasis Research Laboratory of the University of Liege are investigating the effect of these molecules on AML as well as other biological functions associated with HDAC8.
The results will appear in the March issue of the journal Bioorganic and Medicinal Chemistry Letters as well as in U.S. and EU patent applications.
