Histone deacetylases: a new class of efficient anti-tumor drugs

Circa twenty-five years ago, cancer research was dominated by the concept that the origin of cancer was genetic. Thousands of genetic alterations have indeed been identified involving more than hundred different genes in cancer development. Today, the model has evolved: it has been demonstrated that malignancies can be initiated not only through genetic alterations but also through epigenetic deregulations. By altering the expression of gene involved in cell regulation, epigenetic alterations, such as histone acetylation, play a key role in the initiation and progression of neoplasm. It has been shown that an imbalance between the acelylated and deacetylated status of chromatin is significantly involved in the acquisition of a malignant phenotype. Thus, the modulation of the histone acetylation level by histone deacetylase (HDAC) inhibitors could lead to a genetic re-programmation in cancer cells that would favor apoptosis and prevent proliferation. The potential therapeutic value of several HDAC inhibitors for cancer patients has been evaluated in clinical assays with very promising outcome. Indeed, the first inhibitors available for patients has been recently approved for cancer patients tracing the way for a new class of promising anti-cancer therapy modalities.     

赖氨酸特异性组蛋白去甲基化酶1与白血病的研究进展

表观遗传学是后基因组时代兴起的一门新学科,它使人们认识到包括DNA甲基化、组蛋白修饰、染色质重塑及非编码RNA调控在内的修饰也可以记载遗传信息;并且许多表观遗传改变是可逆的,对表观遗传修饰和调控的研究已成为生命科学的热点和发展前沿。2004年发现的赖氨酸特异性组蛋白去甲基化酶1(LSD1)是第一个真正意义上的组蛋白赖氨酸去甲基化酶,使人们认识到组蛋白甲基化是一个动态的过程,通过组蛋白甲基转移酶和去甲基化酶的相互作用,动态地调控基因转录的激活和抑制等生物学过程。这重新定义了组蛋白甲基化,同时也为进一步深入研究组蛋白修饰提供了新的途径。我们在此简要介绍LSD1的结构与功能、LSD1与白血病的关系,LSD1在白血病的发生和发展中发挥重要作用,是一个潜在的治疗白血病的靶基因。     

An epigenetic code for DNA damage repair pathways?

Exposure of living cells to intracellular or external mutagens results in DNA damage. Accumulation of DNA damage can lead to serious consequences because of the deleterious mutation rate resulting in genomic instability, cellular senescence, and cell death. To counteract genotoxic stress, cells have developed several strategies to detect defects in DNA structure. The eukaryotic genomic DNA is packaged through histone and nonhistone proteins into a highly condensed structure termed chromatin. Therefore the cellular enzymatic machineries responsible for DNA replication, recombination, and repair must circumvent this natural barrier in order to gain access to the DNA. Several studies have demonstrated that histone/chromatin modifications such as acetylation, methylation, and phosphorylation play crucial roles in DNA repair processes. This review will summarize the recent data that suggest a regulatory role of the epigenetic code in DNA repair processes. We will mainly focus on different covalent reversible modifications of histones as an initial step in early response to DNA damage and subsequent DNA repair. Special focus on a potential epigenetic histone code for these processes will be given in the last section. We also discuss new technologies and strategies to elucidate the putative epigenetic code for each of the DNA repair processes discussed.     

HDAC modulation and cell death in the clinic

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two opposing classes of enzymes, which finely regulate the balance of histone acetylation affecting chromatin packaging and gene expression. Imbalanced acetylation has been associated with carcinogenesis and cancer progression. In contrast to genetic mutations, epigenetic changes are potentially reversible. This implies that epigenetic alterations are amenable to pharmacological interventions. Accordingly, some epigenetic-based drugs (epidrugs) have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for cancer treatment. Here, we focus on the biological features of HDAC inhibitors (HDACis), analyzing the mechanism(s) of action and their current use in clinical practice.     

Histone Deacetylases: A Saga of Perturbed Acetylation Homeostasis in Cancer

In the current era of genomic medicine, diseases are identified as manifestations of anomalous patterns of gene expression. Cancer is the principal example among such maladies. Although remarkable progress has been achieved in the understanding of the molecular mechanisms involved in the genesis and progression of cancer, its epigenetic regulation, particularly histone deacetylation, demands further studies. Histone deacetylases (HDACs) are one of the key players in the gene expression regulation network in cancer because of their repressive role on tumor suppressor genes. Higher expression and function of deacetylases disrupt the finely tuned acetylation homeostasis in both histone and non-histone target proteins. This brings about alterations in the genes implicated in the regulation of cell proliferation, differentiation, apoptosis and other cellular processes. Moreover, the reversible nature of epigenetic modulation by HDACs makes them attractive targets for cancer remedy. This review summarizes the current knowledge of HDACs in tumorigenesis and tumor progression as well as their contribution to the hallmarks of cancer. The present report also describes briefly various assays to detect histone deacetylase activity and discusses the potential role of histone deacetylase inhibitors as emerging epigenetic drugs to cure cancer.     

黑色素瘤发生发展中的表观遗传学调控

人恶性黑色素瘤(malignant melanoma)是近年来高发病率和高死亡率的肿瘤之一.目前尚缺乏有效的治疗方法.而表观遗传如DNA甲基化(DNA methylation)、组蛋白修饰(histonemodification)、染色质重塑(chromatin remodeling)及RNA干扰(RNA interference,RNAi)等改变在人黑色素瘤的发生、发展和转移中有重要作用.阐明黑色素瘤发生发展的表观遗传学机制已引起了学者的普遍关注.本文综述了人类黑色素瘤发生发展中所特异的表观遗传改变:CpG岛的异常甲基化修饰、组蛋白甲基化和乙酰化修饰、染色质重塑以及microRNA在黑色素瘤发生和转移中的作用,并对应用表观遗传修饰治疗人类黑色素瘤进行了探讨.     

Regulation of global acetylation in mitosis through loss of histone acetyltransferases and deacetylases from chromatin

Histone acetylation, a reversible modification of the core histones, is widely accepted to be involved in remodeling chromatin organization for genetic reprogramming. Histone acetylation is a dynamic process that is regulated by two classes of enzymes, the histone acetyltransferases (HATs) and histone deacetylases (HDACs). Although promoter-specific acetylation and deacetylation has received most of the recent attention, it is superimposed upon a broader acting and dynamic acetylation that profoundly affects many nuclear processes. In this study, we monitored this broader histone acetylation as cells enter and exit mitosis. In contrast to the hypothesis that HATs and HDACs remain bound to mitotic chromosomes to provide an epigenetic imprint for postmitotic reactivation of the genome, we observed that HATs and HDACs are spatially reorganized and displaced from condensing chromosomes as cells progress through mitosis. During mitosis, HATs and HDACs are unable to acetylate or deacetylate chromatin in situ despite remaining fully catalytically active when isolated from mitotic cells and assayed in vitro. Our results demonstrate that HATs and HDACs do not stably bind to the genome to function as an epigenetic mechanism of selective postmitotic gene activation. Our results, however, do support a role for spatial organization of these enzymes within the cell nucleus and their relationship to euchromatin and heterochromatin postmitotically in the reactivation of the genome.     

Histone modifications as a pathogenic mechanism of colorectal tumorigenesis

Epigenetic regulation of gene expression has provided colorectal cancer (CRC) pathogenesis with an additional trait during the past decade. In particular, histone post-translational modifications set up a major component of this process dictating chromatin status and recruiting non-histone proteins in complexes formed to "handle DNA". In CRC, histone marks of aberrant acetylation and methylation levels on specific residues have been revealed, along with a plethora of deregulated enzymes that catalyze these reactions. Mutations, deletions or altered expression patterns transform the function of several histone-modifying proteins, further supporting the crucial role of epigenetic effectors in CRC oncogenesis, being closely associated to inactivation of tumor suppressor genes. Elucidation of the biochemical basis of these new tumorigenic mechanisms allows novel potential prognostic factors to come into play. Moreover, the detection of these changes even in early stages of the multistep CRC process, along with the reversible nature of these mechanisms and the technical capability to detect such alterations in cancer cells, places this group of covalent modifications as a further potential asset for clinical diagnosis or treatment of CRC. This review underlines the biochemistry of histone modifications and the potential regulatory role of histone-modifying proteins in CRC pathogenesis, to date. Furthermore, the underlying mechanisms of the emerging epigenetic interplay along with the chemical compounds that are candidates for clinical use are discussed, offering new insights for further investigation of key histone enzymes and new therapeutic targets.     

Krebs cycle dysfunction shapes epigenetic landscape of chromatin: Novel insights into mitochondrial regulation of aging process

Although there is a substantial literature that mitochondria have a crucial role in the aging process, the mechanism has remained elusive. The role of reactive oxygen species, mitochondrial DNA injuries, and a decline in mitochondrial quality control has been proposed. Emerging studies have demonstrated that Krebs cycle intermediates, 2-oxoglutarate (also known as α-ketoglutarate), succinate and fumarate, can regulate the level of DNA and histone methylation. Moreover, citrate, also a Krebs cycle metabolite, can enhance histone acetylation. Genome-wide screening studies have revealed that the aging process is linked to significant epigenetic changes in the chromatin landscape, e.g. global demethylation of DNA and histones and increase in histone acetylation. Interestingly, recent studies have revealed that the demethylases of DNA (TET1-3) and histone lysines (KDM2-7) are members of 2-oxoglutarate-dependent dioxygenases (2-OGDO). The 2-OGDO enzymes are activated by oxygen, iron and the major Krebs cycle intermediate, 2-oxoglutarate, whereas they are inhibited by succinate and fumarate. Considering the endosymbiont origin of mitochondria, it is not surprising that Krebs cycle metabolites can control the gene expression of host cell by modifying the epigenetic landscape of chromatin. It seems that age-related disturbances in mitochondrial metabolism can induce epigenetic reprogramming, which promotes the appearance of senescent phenotype and degenerative diseases.     

Histone modifications and nuclear architecture: a review.

Epigenetic modifications, such as acetylation, phosphorylation, methylation, ubiquitination, and ADP ribosylation, of the highly conserved core histones, H2A, H2B, H3, and H4, influence the genetic potential of DNA. The enormous regulatory potential of histone modification is illustrated in the vast array of epigenetic markers found throughout the genome. More than the other types of histone modification, acetylation and methylation of specific lysine residues on N-terminal histone tails are fundamental for the formation of chromatin domains, such as euchromatin, and facultative and constitutive heterochromatin. In addition, the modification of histones can cause a region of chromatin to undergo nuclear compartmentalization and, as such, specific epigenetic markers are non-randomly distributed within interphase nuclei. In this review, we summarize the principles behind epigenetic compartmentalization and the functional consequences of chromatin arrangement within interphase nuclei.     

Histone acetyltransferases and deacetylases: molecular and clinical implications to gastrointestinal carcinogenesis

Histone acetyltransferases and deacetylases are two groups of enzymes whose opposing activities govern the dynamic levels of reversible acetylation on specific lysine residues of histones and many other proteins. Gastrointestinal (GI) carcinogenesis is a major cause of morbidity and mortality worldwide. In addition to genetic and environmental factors, the role of epigenetic abnormalities such as aberrant histone acetylation has been recognized to be pivotal in regulating benign tumorigenesis and eventual malignant transformation. Here we provide an overview of histone acetylation, list the major groups of histone acetyltransferases and deacetylases, and cover in relatively more details the recent studies that suggest the links of these enzymes to GI carcinogenesis. As potential novel therapeutics for GI and other cancers, histone deacetylase inhibitors are also discussed.     

Computer- and structure-based lead design for epigenetic targets

The term epigenetics is defined as inheritable changes that influence the outcome of a phenotype without changes in the genome. Epigenetics is based upon DNA methylation and posttranslational histone modifications. While there is much known about reversible acetylation as a posttranslational modification, research on reversible histone methylation is still emerging, especially with regard to drug discovery. As aberrant epigenetic modifications have been linked to many diseases, inhibitors of histone modifying enzymes are very much in demand. This article will summarize the progress on small molecule epigenetic inhibitors identified by structure- and computer-based approaches.     

Epi-drugs to fight cancer: from chemistry to cancer treatment, the road ahead

In addition to genetic events, a variety of epigenetic events have been widely reported to contribute to the onset of many diseases including cancer. DNA methylation and histone modifications (such as acetylation, methylation, sumoylation, and phosphorylation) involving chromatin remodelling are among the most studied epigenetic mechanisms for regulation of gene expression leading, when altered, to some diseases. Epigenetic therapy tries to reverse the aberrations followed to the disruption of the balance of the epigenetic signalling ways through the use of both natural compounds and synthetic molecules, active on specific epi-targets. Such epi-drugs are, for example, inhibitors of DNA methyltransferases, histone deacetylases, histone acetyltransferases, histone methyltransferases, and histone demethylases. In this review we will focus on the chemical aspects of such molecules, joined to their effective (or potential) application in cancer therapy.