Cancer is a disease of genetic defects such as gene mutations and deletions as well as chromosomal abnormalities, which together result in the gain of function or hyperactivation of oncogenes, or the loss of function of tumor suppressor genes. Recent evidence indicates, however, that changes in gene expression attributable to epigenetic alterations also contribute to the onset and progression of cancer.(1,2) Remodeling of chromatin between relatively open and closed states plays a key role in the epigenetic regulation of gene expression. Such remodeling is induced by modification of the structure of nucleosomes, which consist of approximately two turns of the DNA helix wound around a histone octamer. Regulation of nucleosome structure is mediated in part by modification of the amino-terminal tail of histones.(3) Acetylation of histones (in particular, histones H3 and H4), which is determined by the opposing activities of histone acetyltransferases (HAT) and histone deacetylases (HDAC), is central to the regulation of gene expression through chromatin modification.(4) HAT transfer acetyl groups to lysine residues in the amino-terminal tail of histones, resulting in local expansion of chromatin and increased accessibility of the DNA to regulatory proteins, whereas HDAC catalyze the removal of acetyl groups, leading to chromatin condensation and transcriptional repression. (6 -8) Reduced levels of histone acetylation as a result of aberrant HDAC activity have thus been detected in several human tumors and appear to trigger repression of tumor suppressor genes and to contribute to tumor onset and progression. (9) Specific inhibition of HDAC activity has therefore emerged as a potential strategy to reverse epigenetic changes associated with cancer. Several small-molecule HDAC inhibitors have recently been shown to exhibit potent and specific anticancer activity in preclinical studies. (10)(11)(12)(13)(14) Multiple mechanisms have been proposed for the anticancer activity of HDAC inhibitors, which include the enhanced acetylation of core histones and consequent increased accessibility of genomic DNA to transcriptional complexes, resulting in the induction of tumor suppressor genes.(10,15) The hyper-acetylation of histones induced by the HDAC inhibitor trichostatin A (TSA) has been shown to increase chromatin accessibility by measurement of the size-dependent nuclear distribution of microinjected fluorescein isothiocyanate-dextran conjugates with the use of image-correlation spectroscopy.(16) Such an HDAC inhibitorinduced relaxation of chromatin structure would be expected to increase chromatin accessibility not only to transcription factors but also to therapeutic agents that target genomic DNA. Consistent with this notion, HDAC inhibitors have been shown to sensitize tumor cells to the induction of cell death by ionizing radiation, (17,18) ultraviolet (UV) radiation, (19) and several DNA-damaging drugs. (20,21) The molecular mechanisms of such effects have remained largely unknown.Anticancer drugs that induce DNA dam...

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