Histone Acetylation Modifiers in the Pathogenesis of Malignant Disease

Molecular Medicine 6(8): 623–644, 2000 Molecular Medicine © 2000 The Picower Institute Press Review Article Histone Acetylation Modifiers in the Pathogenesis of Malignant Disease Ulrich Mahlknecht and Dieter Hoelzer Department of Hematology/Oncology, University of Frankfurt Medical Center, Frankfurt, Germany Abstract Chromatin structure is gaining increasing attention as a potential target in the treatment of cancer. Relaxation of the chromatin fiber facilitates transcription and is regulated by two competing enzymatic activities, histone acetyltransferases (HATs) and histone deacetylases (HDACs), which modify the acetylation state of histone proteins and other promoter-bound transcription factors. While HATs, which are frequently part of multisubunit coactivator complexes, lead to the relaxation of chromatin structure and transcriptional activation, HDACs tend to associate with multisubunit corepressor complexes, which result in chromatin condensation and transcriptional repression of specific target genes. HATs and HDACs are known to be involved both in the pathogenesis as well as in the suppression of cancer. Some of the genes encoding these enzymes have been shown to be rearranged in the context of chromosomal translocations in human acute leukemias and solid tumors, where fusions of regulatory and coding regions of a variety of transcription factor genes result in completely new gene products that may interfere with regulatory cascades controlling cell growth and differentiation. On the other hand, some histone acetylation–modifying enzymes have been located within chromosomal regions that are particularly prone to chromosomal breaks. In these cases gains and losses of chromosomal material may affect the availability of functionally active HATs and HDACs, which in turn disturbs the tightly controlled equilibrium of histone acetylation. We review herein the recent achievements, which further help to elucidate the biological role of histone acetylation modifying enzymes and their potential impact on our current understanding of the molecular changes involved in the development of solid tumors and leukemias. DNA in chromatin is organized in arrays of nucleosomes, where two copies of each histone protein—H2A, H2B, H3, and H4—are assembled into an octamer that has approximately 146 base pairs of DNA wrapped around it in 1.8 turns to form a nucleosome. The nucleosome is an invariant component of euchromatin and hete- rochromatin in the interphase nucleus, and of mitotic chromosomes. This highly conserved nucleoprotein complex occurs fundamentally every 200  40 bp throughout all eukaryotic genomes (1). During mitosis, the tightly packed metaphase chromosomes need to be accurately distributed between two daughter cells, while the DNA has to be accessible to various enzymatic machineries during interphase, when DNA is replicated, specific parts are transcribed, and mutated DNA segments are repaired. Under these circumstances, the nucleosomal architecture represents a major structural obstacle that Address correspondence and reprint requests to: Ulrich Mahlknecht, MD, PhD, University of Frankfurt Medical Center, Department of Hematology/Oncology, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany. Phone: +49-69-6301-5235. Fax: +49-69-6301-6131. E-mail: 624 Molecular Medicine, Volume 6, Number 8, August 2000 limits the access of factors to nucleosomebound DNA (2). The interaction of DNA with histone proteins is highly complex and may— at least in part—be explained by electrostatic interactions between negatively charged phosphate groups in the DNA backbone and positively charged amino acids in the histone proteins (3–5). A number of post-translational modifications of the histone components of chromatin, including acetylation, phosphorylation, ubiquitination, methylation, and ADPribosylation, which altogether affect transcriptional regulation, have been described (6–8). However, our focus in this review is on the role of histone modification through acetylation in the pathogenesis of cancer. First observations linking transcriptional activity with histone acetylation and deacetylation of the -amino groups of conserved lysine residues, which are present in the amino terminal tails of all four core histones (H2A, H2B, H3, and H4), were made more than three decades ago (9). These observations have been reinforced by studies that demonstrated transcriptionally active euchromatin domains to be highly acetylated and/or hypomethylated (9–12), while densely methylated inactive DNA has been associated with hypoacetylated histone proteins (9,13,14). Notably, most DNA in mammals is methylated at CpG dinucleotides, with the exception of promoter elements, which contain undermethylated CpG islands (15). MethylCpG binding protein 2 (MeCP2) is a protein that recognizes methylated DNA and interacts with histone deacetylases, which are part of the mSIN3A/histone deacetylases (HDAC) multisubunit repressor complex. This suggests that MeCP2 mediates silencing of methylated DNA through deacetylation (16–18) (Fig. 1). It took more than three decades to test the validity of the hypothesis that linked transcriptional activity with the post-translational modification of histone proteins, following the identification of the regulators of histone acetylation, histone acetyltransferases, and histone deacetylases (19). These enzymes allow reversible modification of histone proteins through the addition or removal of acetyl groups, which alter the strength of the bonding between histones and DNA, thereby modifying the regulation of biological processes such as DNA replication and repair, gene expression, chromatin assembly, condensation, and cell division (see also 20,21 for reviews). In addition to the effect of histone acetyltransferases (HATs) and HDACs on the charge of the histone octamer, these enzymes may also directly alter the activity of basal and sequence-specific transcription factors as well as other cellular regulators (cell-cycle regulators, signaling cascades, etc.) (Fig. 2) (5,22,23). Histone Modification and Transcriptional Control The work of many investigators during the last few years has contributed to almost explosive advances in our understanding of the molecular details of transcriptional regulation and chromatin modification within the context of the highly complex interplay of protein–DNA binding factors and protein–protein interactions. It is now becoming increasingly obvious that most enzymes that regulate the acetylation state of histone proteins and other promoterbound transcription factors (i.e., HATs and HDACs) exert their enzymatic activities as members of large multisubunit protein complexes. A deregulation of the tightly controlled equilibrium of acetylation and deacetylation plays a causative role in the generation as well as in the suppression of several types of cancer (20,24–27). Depending on the specific target promotors, hyperacetylation and deacetyl (...truncated)