The involvement of histone acetylation and deacetylation in so many aspects of development and tissue homeostasis might suggest that systemic inhibition of HDACs with pharmacologic inhibitors would result in nonspecific and catastrophic effects as a consequence of global derepression of gene expression. Thus, it is striking that systemic HDAC inhibition with compounds that broadly inhibit most or all HDACs is well tolerated in vivo and blocks numerous disease-associated gene expression programmes in a seemingly specific manner.
Given the dramatic phenotypes that result from HDAC gene deletions, why are HDAC inhibitors so well tolerated in vivo? we propose three explanations, which are not mutually exclusive. First, a genetic deletion of an HDAC results in the complete absence of the enzyme, whereas inhibitors do not result in complete inhibition of activity. Second, a genetic deletion of an HDAC eliminates the gene product permanently, whereas the actions of an inhibitor are transient. Third, and perhaps most importantly, HDACs participate in multiprotein transcriptional complexes. Genetic deletion of an HDAC perturbs the complexes in which it would normally be associated, whereas inhibitors are believed to block enzymatic activity without necessarily disrupting the repressive complex.
Classical HDAC inhibitors such as trichostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA) are mostly ‘pan–HDAC’ inhibitors; that is, they block, with similar affinities, the activity of all isoforms except class IIa HDACs. For example, the IC50
values for SAHA are: HDAC1 = 37.1 nM; HDAC3 = 44.6 nM; and HDAC6 = 40.9 nM90
. Given that different HDAC isoforms govern dramatically different gene expression programmes in development and disease, it seems plausible that isoform-selective inhibitors should lead to improved efficacy and drug safety. The recent mechanistic insights into the biochemistry of class IIa HDACs should also be taken into account36,41,91
. Many screening studies used class IIa HDACs purified from mammalian cells for the development of class IIa isoform-specific inhibitors and, surprisingly, compounds were identified that blocked class IIa but not class I activity. These compounds probably function as small-molecule inhibitors of protein–protein interactions and not as bona fide HDAC inhibitors92
. As these molecules are entering clinical trials, it is important to realize that they might show biological properties distinct from classical HDAC inhibitors.
HDAC inhibitors from multiple chemical classes have entered clinical trials, and SAHA (marketed as Vorinostat, brand name Zolinza) has been approved for treatment of cutaneous manifestations of advanced, refractory T-cell lymphoma in a select group of patients93
. The exact mechanism for the effect of HDAC inhibitors on tumour cells is currently unknown, and numerous explanations, such as changes in gene transcription, direct induction of apoptosis, production of reactive oxygen species and induction of cell-cycle arrest, have been proposed92,94–96
. The specific HDAC isoforms that mediate this antiproliferative effect also remain to be clearly identified. Genetic deletion of HDAC3 leads to cell-cycle dependent DNA damage coupled with defective double-stranded break repair70
. HDAC3-null cells are thus sensitized to ionizing radiation, a phenomenon that has also been observed with HDAC inhibitors97
. Therefore, some of the effects observed with HDAC inhibition might be mediated via HDAC3, although the involvement of other isoforms can not be ruled out98
. The existence of conditional alleles for all class I HDACs might allow the creation of transformed cancer cell lines with conditional alleles for all the different class I HDAC isoforms (and their combinations), which would make a systematic analysis of HDAC requirement in cancer cells possible. These studies could then be extended by crossing conditional HDAC-null alleles into tumour-prone genetic backgrounds.
One of the most perplexing aspects of HDAC biology is that pharmacological inhibition of HDAC activity provides a therapeutic benefit in such a wide variety of disease states. gives an overview of the disease states in which HDAC inhibition has been shown to be beneficial as well as the proposed mechanisms involved. These range from infectious and immunological diseases to traumatic shock, and from cardiac hypertrophy to neurodegenerative disease99–105
, and in certain circumstances HDAC inhibitors are even able to ‘cure’ genetic disease in humans106
. Although a unifying theory explaining how reduced deacetylase activity is beneficial in such diverse pathophysiological states is currently unknown, it is tempting to speculate that most of these diseases have an epigenetic component (that is, aberrant histone acetylation), and that treatment with HDAC inhibitors resets the epigenetic memory of the cell to a pre-disease state.
Clinical and experimental use of histone deacetlyase (HDAC) inhibitors in diverse disease states