Epigenetic therapy: targeting histones and their modifications in human disease
2010; Future Science Ltd; Volume: 2; Issue: 4 Linguagem: Inglês
10.4155/fmc.10.18
ISSN1756-8927
AutoresAkash Gunjan, Rakesh Kumar Singh,
Tópico(s)Histone Deacetylase Inhibitors Research
ResumoFuture Medicinal ChemistryVol. 2, No. 4 EditorialFree AccessEpigenetic therapy: targeting histones and their modifications in human diseaseAkash Gunjan & Rakesh Kumar SinghAkash Gunjan† Author for correspondenceDepartment of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call Street, Tallahassee, FL, 32306-4300, USA. & Rakesh Kumar Singh Published Online:6 Apr 2010https://doi.org/10.4155/fmc.10.18AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Histones are essential eukaryotic proteins that were discovered in 1884 by Albrecht Kossel as the main protein component of the nuclei [1]. Two molecules of each of the four core histones (H2A, H2B, H3 and H4) constitute the histone octamer, around which 147bp of DNA are wrapped to form the nucleosome core particle, the fundamental repeating unit of eukaryotic chromatin [2]. A linker histone, also known as histone H1, is present in higher eukaryotes and seals two full turns of the DNA to form the complete nucleosome. This nucleosomal structure is repeated until the entire genomic DNA is packaged into chromatin fibers that undergo further compaction to form chromosomes. Despite over a century of histone research, only over the past two decades have researchers come to appreciate that histones and chromatin structure regulate access to the information contained within the DNA and, as such, influence all metabolic processes that require access to the DNA, including transcription, replication, recombination and DNA damage and repair. In doing so, histones and chromatin structure are likely to impact upon normal human physiology, as well as disease processes such as cancer and aging. Furthermore, following the discovery of a plethora of post-translational modifications of histones that play a regulatory role in almost all chromatin transactions, the classic viewpoint that histones act as mere structural components of chromatin has been substantially modified in recent years. Core histones have been shown to be phosphorylated, acetylated, methylated, sumoylated, ribosylated and ubiquitylated at various amino acid residues, forming a 'histone code' that plays a pivotal role in regulating access to the genetic information contained in the DNA [3]. The histone code hypothesis postulates that histone modifications not only alter the affinity of histones for DNA but, more importantly, they also serve as binding sites for specific factors that are capable of transducing multiple down-stream effects. The histone code, along with DNA methylation, is collectively referred to as the 'epigenetic code'. Crosstalk between these modifications has been well documented, especially in case of methylation, acetylation and phosphorylation [4]. Epigenetic alterations have now been linked to numerous human disorders, treatment for which has been aptly termed 'epigenetic therapy'. Histone and DNA modifications are carried out by numerous enzymes that have been the subject of intense investigation recently, particularly as potential therapeutic targets in human diseases [5]. In this editorial, we will focus on the current state of knowledge regarding histone modifications, as well as unmodified histones as potential future drug targets for the treatment of human diseases.Newly synthesized histones are extensively acetylated by histone acetyltransferases (HATs) on lysine (K) residues and this acetylation can be removed by a group of enzymes known as histone deacetylases (HDACs) [6]. The acetyl group in the acetylation reaction is generally contributed by acetyl coenzyme A and deacetylases reverse this reaction by transferring the acetyl groups back to coenzyme A. Since the acetyl group is negatively charged, acetylation leads to the neutralization of a positive charge on the lysine residues of histones, which in turn weakens the interaction of positively charged histones with negatively charged phosphate groups on DNA, thereby relaxing the chromatin. This relaxed chromatin is generally associated with higher transcriptional activity. Deacetylation reverses this chromatin relaxation and leads to more compact chromatin, which is generally transcriptionally inactive. Numerous diseases, including neurological disorders and several types of cancer, are believed to be defective in this regulatory epigenetic mechanism involving reversible acetylation. Hence, the enzymes regulating reversible acetylation, particularly the HDACs, are potential therapeutic targets. A classic HDAC inhibitor, valproic acid, has been used for more than three decades in the treatment of several neurological disorders ranging from epilepsy to bipolar disorder and schizophrenia, and, more recently, as a prophylaxis for migraines [7]. However, it is possible that the beneficial effects of valproic acid observed in these disorders are not solely related to its HDAC-inhibiting activity, but other effects of this drug on neurological processes as well. In recent years, several novel classes of HDAC inhibitors have been described [8], many of which are in different phases of clinical trials targeting different types of cancers. The first of these new HDAC inhibitors, vorinostat (suberoylanilide hydroxamic acid), has received US FDA approval for treating patients with cutaneous T-cell lymphoma (CTCL). More recently, another HDAC inhibitor, romidepsin (depsipeptide, a natural product obtained from bacteria) was also approved for treating CTCL.Sirtuins are novel class of HDACs that require nicotinamide adenine dinucleotide (NAD+) for their HDAC activity [9]. As such, some sirtuins, particularly SIRT1, are thought to be involved in maintaining energy homeostasis in the cells and are crucial regulators of aging in several organisms. Various small-molecule modulators of sirtuin activity [10], such as resveratrol, a natural compound found in plants that is also present in red wine [11], appear to hold great promise for combating a variety of human disorders from metabolic syndrome and type II diabetes to cancer and aging [12,13]. The sirtuin modulators appear to alter numerous physiological pathways to bring about an overall beneficial health effect on model organisms; however, more research needs to be carried out to determine if and at what concentrations they will be beneficial for human health [9].Histone acetyltransferase activity has also been found to be altered in several diseases. For example, mutations in the HAT domain of cAMP-responsive element binding (CREB)-binding protein (CBP) can lead to Rubinstein–Taybi syndrome [14]. Another HAT enzyme, amplified-in-breast cancer 1 (AIB1) is known to be overexpressed in breast, ovarian and gastric cancers [15], while translocation of HAT genes has been implicated in acute myelogenous leukemia [16]. Furthermore, mutations of the HAT p300 have been reported in human colorectal, gastric, breast and pancreatic cancers [17,18]. In a step towards targeting aberrant HAT activity, researchers have successfully synthesized 28 HAT inhibitors that showed approximately 95% inhibition of HATs and were specifically cytotoxic towards several cancer cell lines without showing any significant toxicity towards normal cells [19]. Moreover, follow-up studies would reveal whether any of these inhibitors could progress to clinical trials in the future. Hence, although research into HAT inhibitors is currently in its infancy, it holds great promise for future treatment regimes for multiple disorders.Histone methyltransferases (HMTs) transfer methyl groups to either K or R residues of histones. Histone methylation is known to regulate heterochromatin formation, X-chromosome inactivation, genetic imprinting, transcription and DNA repair [20]. Lysine residues can be mono-, di- or tri-methylated whereas R residues could be mono- or di-methylated. R methylation generally correlates with transcriptional activation [21]; however, K methylation can lead to either transcriptional activation or repression, depending on the K residue. In general, histone H3-K4, H3-K36 and H3-K79 methylation has been linked to transcriptional activation [22], whereas H3-K9, H3-K27 and H4-K20 methylation is associated with the repression of euchromatic genes [23,24]. However, the biological consequence of the methylation of the same lysine residue could be different depending on the methylation state [25]. For example, trimethylation of H3-K9 has been linked both to transcriptional silencing and activation [26]. The HMTs use S-adenosylmethionine as a cosubstrate for the transfer of the methyl group. Methylation influences the basicity as well as hydrophobicity of histones and their affinity towards certain proteins, such as transcription factors. Over 70 methyltransferases are encoded by the human genome [27–29], many of which have been implicated in cancer. Hence, these enzymes are emerging as potential targets for cancer therapy. Chaetosin [30] and BIX-01294 [31] are two promising HMT inhibitors that have been shown to inhibit lysine methyltransferases Su(var)3-9 and G9a, respectively. Researchers in Germany followed a target-based approach to discover inhibitors of histone arginine methyltransferases [32]. In this study they discovered two compounds, stilbamidine and allantodapsone, which have shown hypomethylating effects in HepG2 cells. Future studies based on such targeted approaches hold great promise for finding additional candidate small-molecule inhibitors of additional HMTs, some of which are likely to enter clinical trials.For several decades, histone methylation was generally considered to be static, based on similar turnover rates of histones and the methyl groups on histone K and R residues in mammalian cells [33,34]. However, identification of the first histone demethylase, LSD1, in 2004 [35] changed this dogma and led to the discovery of several histone demethylases. LSD1 is an amine oxidase that catalyzes lysine demethylation in a flavin adenine dinucleotide (FAD)-dependent manner. LSD1 can demethylate mono- and di-methyl (but not tri-methyl) marks on histone H3 at K4 and K9. A second class of histone demethylases was subsequently discovered, consisting of a large protein family of the Jumonji C (JmjC) domain-containing proteins [36]. The demethylation reaction carried out by JmjC domain proteins requires the presence of Fe(II) and α-ketoglutarate to generate formaldehyde and succinate and allows removal of mono-, di- and tri-methylated lysines. Since several types of cancer are characterized by the epigenetic silencing of tumor suppressor genes, often mediated by aberrant histone methylation, it is hardly surprising that a recent report suggested that LSD1 might serve as a novel biomarker predictive of aggressive prostate cancer. Hence, histone demethylases are also potential therapeutic cancer targets. Inhibition of LSD1 by polyamine analogs have been found to reverse aberrant gene silencing [37]. In a subsequent study, the same group explored another class of polyamine analogues, the oligoamines, which inhibit polyamine oxidases and have high affinity for DNA, based on the increased number of positively charged nitrogens compared with the biguanide and bisguanidine analogues [38]. The oligoamine analogues were found to be competitive inhibitors of recombinant LSD1, suggesting that the oligoamines may compete directly with the substrate at the active site in vivo. This inhibitor of histone demethylases was found to block colon tumor-cell growth coincident with histone methylation and gene re-expression [38]. Interestingly, it also markedly potentiated the activity of DNA hypomethylating agents in vitro and in vivo, suggesting that histone demethylase inhibitors may synergize with DNA methylation inhibitors and, thus, represent a class of potential epigenetic therapeutic agents that can be used in combination therapy to treat human disease.Histone H2A was the first protein known to be ubiquitylated [39]. Subsequently, the mechanistic details of the essential ubiquitin–proteasome system for the degradation of polyubiquitylated proteins was discovered, while nondegradation-related regulatory roles were attributed to the monoubiquitylation of some proteins [40]. Over the past three decades, all core histones have been shown to be ubiquitylated in one or more ways, although, with a few exceptions, the functional significance of most histone ubiquitylation remains unclear [41]. Histone H2B has been found to be monoubiquitylated in many species and functions in the control of transcriptional activation by regulating the methylation of certain K residues on histone H3 [42]. H3 and H4 ubiquitylation has been shown to facilitate the cellular response to DNA damage [43]. In a recent report, Geng and Tansey showed that H2B was extensively polyubiquitylated in chromatin, although this polyubiquitylation was not associated with H2B degradation [44]. We have recently shown that nonchromatin-bound 'excess' histones are rapidly degraded in a Rad53 kinase-dependent manner in budding yeast [45,46]. We believe that phosphorylation of Y99 on histone H3, followed by subsequent ubiquitylation by the ubiquitin-conjugating enzymes Ubc4/Ubc5, in concert with the ubiquitin ligase Tom1, triggers H3 degradation. We have also presented evidence to show that histone H4 is degraded in a phosphorylation- and ubiquitylation-dependent manner. Future studies are likely to find that H2A and H2B are also regulated by ubiquitylation-dependent proteolysis. These histone degradation mechanisms are of paramount significance, as any excess of histones is toxic to the cell [46,47]. We found that mutating the genes involved in H3/H4 degradation led to an increase in the DNA-damage sensitivity as well as genomic instability in yeast cells. Since genomic instability is a hallmark of cancer cells, dysfunctional histone regulation may be a contributing factor in carcinogenesis and other genomic instability disorders. So far, a histone proteolytic pathway has not been elucidated in somatic mammalian cells. However, since histone genes are present in higher copy numbers in mammals, compared with only two copies of each core histone gene in budding yeast, mammalian cells are even more likely to experience problems related to excess histones and are very likely to have similar pathways for dealing with excess histones. Interestingly, the human homolog of the yeast Rad53 is the tumor suppressor checkpoint kinase CHEK2 that has been found to be mutated in several human cancers [48], while the human homolog of yeast, Tom1, is the E3 ligase HUWE1, which has been shown to ubiquitylate histones [49] and regulate levels of the pre-eminent tumor suppressor p53 (a downstream target of CHEK2 in the DNA-damage-response pathway). Not surprisingly, abnormal levels of HUWE1 have been found in breast and lung cancers [50] and it has been suggested as a potential drug target in both p53-negative and -positive cancers [51]. Further studies are required to determine the involvement, if any, of CHEK2 and HUWE1 in general histone turnover and determine the importance of this function in the maintenance of genomic stability in human cells. We are currently exploring the existence of histone proteolytic pathways in human cells, where their dysfunction may turn out to be important in several pathologies, thus serving as important drug targets in the future. Since the presence of excess histones makes cells more sensitive to DNA-damaging agents [45,46], some of which serve as an important class of current anticancer drugs [52], potential inhibitors of histone-regulatory pathways may be used in conjunction with this class of chemotherapeutic agents to further potentiate their effect at significantly lower doses, thus minimizing their side effects.Although much of the current effort in drug development are directed towards histone modifications, unmodified histone proteins can by themselves be drug targets for some human conditions. Histones were shown to have antimicrobial activity by James Hirsch [53] and, later, by several other research groups. They were shown to be more potent in killing bacteria than canonical antibiotics. In a recent report, Xu et al. showed that histones can also kill human cells under certain conditions [54]. In trying to find the cause of sepsis (the tenth leading cause of death in the USA), they discovered that histones released from the cells were the main cause of the global hyperinflammatory response and the ensuing multiple organ failure. They found that injecting anti-H4 antibodies protected mice in three different models of sepsis: injection of lipopolysaccharide, injection of TNF and a cecal ligation and puncture model. At the very least these findings may point to the exciting possibility that the highly specific monoclonal histone antibodies that are currently available may be used to counteract death due to sepsis in the near future. However, caution should be exercised in using histone antibodies for therapeutics, as histone autoantibodies are often associated with autoimmune disorders such as systemic lupus erythromatus [55].Several questions must be addressed before the full therapeutic potential of epigenomics can be realized. We still do not fully understand how histone-modification patterns are established during development and how they are passed on from one generation to the next. Systematic mapping of histone modification marks during embryonic development and cell differentiation might shed some light on the epigenetic mechanisms involved throughout development. The first comprehensive genome-scale histone methylation mapping has already suggested novel functions of known histone methylation marks in T-cells [56]. It has also discovered H2B monomethylation on K5 as a new methylation mark. Another study mapped genome-wide distribution of histone trimethylation marks in mouse embryonic stem cells and lineage-committed cells [57]. Advancement in genome-sequencing technologies and epigenome-mapping projects are likely to revolutionize the field of epigenomics and medicine alike in the near future. These high-throughput techniques hold great promise for elucidating the crosstalk between histone-modification networks and their role in transcriptional regulation during normal development and disease progression. Structural studies on histone-modifying enzymes and elucidation of their interaction partners will certainly lead to the identification of additional targets for future drug-development efforts. Most importantly, since histone- and DNA-modifying enzymes exhibit moderate to high substrate specificity and appear to be targeted to specific loci in the genome, it is possible that combinations of different small-molecule modifiers of these enzymes would permit a powerful and flexible method to combat very diverse human disorders in the future, based on the same basic premise of modulating epigenetics. 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