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Cold Spring Harbor Perspectives in... Apr 2014Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In... (Review)
Review
Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In humans, there are 18 HDAC enzymes that use either zinc- or NAD(+)-dependent mechanisms to deacetylate acetyl lysine substrates. Although removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, deacetylation of nonhistones controls diverse cellular processes. HDAC inhibitors are already known potential anticancer agents and show promise for the treatment of many diseases.
Topics: Arginase; Gene Expression Regulation; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Models, Biological; Protein Processing, Post-Translational; Protein Structure, Tertiary; Saccharomyces cerevisiae; Sirtuins; Substrate Specificity
PubMed: 24691964
DOI: 10.1101/cshperspect.a018713 -
The Biochemical Journal Mar 2003Transcriptional regulation in eukaryotes occurs within a chromatin setting, and is strongly influenced by the post-translational modification of histones, the building... (Review)
Review
Transcriptional regulation in eukaryotes occurs within a chromatin setting, and is strongly influenced by the post-translational modification of histones, the building blocks of chromatin, such as methylation, phosphorylation and acetylation. Acetylation is probably the best understood of these modifications: hyperacetylation leads to an increase in the expression of particular genes, and hypoacetylation has the opposite effect. Many studies have identified several large, multisubunit enzyme complexes that are responsible for the targeted deacetylation of histones. The aim of this review is to give a comprehensive overview of the structure, function and tissue distribution of members of the classical histone deacetylase (HDAC) family, in order to gain insight into the regulation of gene expression through HDAC activity. SAGE (serial analysis of gene expression) data show that HDACs are generally expressed in almost all tissues investigated. Surprisingly, no major differences were observed between the expression pattern in normal and malignant tissues. However, significant variation in HDAC expression was observed within tissue types. HDAC inhibitors have been shown to induce specific changes in gene expression and to influence a variety of other processes, including growth arrest, differentiation, cytotoxicity and induction of apoptosis. This challenging field has generated many fascinating results which will ultimately lead to a better understanding of the mechanism of gene transcription as a whole.
Topics: Acetylation; Evolution, Molecular; Gene Expression Regulation; Histone Deacetylases; Histones; Humans; Isoenzymes; Models, Genetic; Molecular Structure; Neoplasms; Repressor Proteins; Signal Transduction; Tissue Distribution; Transcription, Genetic
PubMed: 12429021
DOI: 10.1042/BJ20021321 -
Molecular Oncology Dec 2012Reversible acetylation of histone and non-histone proteins is one of the most abundant post-translational modifications in eukaryotic cells. Protein acetylation and... (Review)
Review
Reversible acetylation of histone and non-histone proteins is one of the most abundant post-translational modifications in eukaryotic cells. Protein acetylation and deacetylation are achieved by the antagonistic actions of two families of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). Aberrant protein acetylation, particularly on histones, has been related to cancer while abnormal expression of HDACs has been found in a broad range of cancer types. Therefore, HDACs have emerged as promising targets in cancer therapeutics, and the development of HDAC inhibitors (HDIs), a rapidly evolving area of clinical research. However, the contributions of specific HDACs to a given cancer type remain incompletely understood. The aim of this review is to summarize the current knowledge concerning the role of HDACs in cancer with special emphasis on what we have learned from the analysis of patient samples.
Topics: Acetylation; Animals; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Histone Deacetylases; Histones; Humans; Neoplasms
PubMed: 22963873
DOI: 10.1016/j.molonc.2012.07.003 -
Arteriosclerosis, Thrombosis, and... Sep 2015Cardiometabolic disease, emerging as a worldwide epidemic, is a combination of metabolic derangements leading to type 2 diabetes mellitus and cardiovascular disease.... (Review)
Review
Cardiometabolic disease, emerging as a worldwide epidemic, is a combination of metabolic derangements leading to type 2 diabetes mellitus and cardiovascular disease. Genetic and environmental factors are linked through epigenetic mechanisms to the pathogenesis of cardiometabolic disease. Post-translational modifications of histone tails, including acetylation and deacetylation, epigenetically alter chromatin structure and dictate cell-specific gene expression patterns. The histone deacetylase family comprises 18 members that regulate gene expression by altering the acetylation status of nucleosomal histones and by functioning as nuclear transcriptional corepressors. Histone deacetylases regulate key aspects of metabolism, inflammation, and vascular function pertinent to cardiometabolic disease in a cell- and tissue-specific manner. Histone deacetylases also likely play a role in the metabolic memory of diabetes mellitus, an important clinical aspect of the disease. Understanding the molecular, cellular, and physiological functions of histone deacetylases in cardiometabolic disease is expected to provide insight into disease pathogenesis, risk factor control, and therapeutic development.
Topics: Animals; Cardiovascular Diseases; DNA; Gene Expression Regulation; Histone Deacetylases; Humans
PubMed: 26183616
DOI: 10.1161/ATVBAHA.115.305046 -
Sheng Li Xue Bao : [Acta Physiologica... Feb 2022Histone acetylation is one of the epigenetic modifications. Histone acetylation, which is catalyzed by histone acetyltransferases and negatively regulated by histone... (Review)
Review
Histone acetylation is one of the epigenetic modifications. Histone acetylation, which is catalyzed by histone acetyltransferases and negatively regulated by histone deacetylases, plays an important role in a variety of cellular physiological and pathophysiological processes. Recent studies have shown that histone deacetylases are involved in a variety of pathophysiological responses to acute kidney injury, such as apoptosis, dedifferentiation, proliferation and regeneration. This article reviews the role and underlying mechanism of histone deacetylases in acute kidney injury induced by ischemia reperfusion, nephrotoxicants, sepsis and rhabdomyolysis.
Topics: Acetylation; Acute Kidney Injury; Histone Acetyltransferases; Histone Deacetylases; Humans; Protein Processing, Post-Translational
PubMed: 35199128
DOI: No ID Found -
Current Opinion in Structural Biology Dec 2019Zinc-dependent histone deacetylases (HDACs) regulate the biological function of histone and non-histone proteins through the hydrolysis of acetyllysine side chains to... (Review)
Review
Zinc-dependent histone deacetylases (HDACs) regulate the biological function of histone and non-histone proteins through the hydrolysis of acetyllysine side chains to yield free lysine and acetate. Certain HDAC isozymes exhibit alternative catalytic activities, such as polyamine deacetylase or lysine fatty acid deacylase activity. To date, crystal structures have been reported for class I HDACs (1, 2, 3, and 8), class IIa HDACs (4 and 7), and class IIb HDACs (6 and 10). Conserved active site residues mediate the chemistry of substrate activation and hydrolysis in these isozymes through a metal-activated water molecule assisted by general base-general acid catalysis. Upregulated HDAC activity is observed in cancer and neurodegenerative disease, and four HDAC inhibitors are currently approved for use in cancer chemotherapy. Crystal structures of HDAC-inhibitor complexes guide the design of new inhibitors with high affinity and selectivity for specific HDAC isozymes implicated in human disease.
Topics: Amides; Catalysis; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydrolysis; Isoenzymes; Models, Molecular; Molecular Conformation; Multigene Family; Protein Binding; Quantitative Structure-Activity Relationship; Substrate Specificity; Zinc
PubMed: 30743180
DOI: 10.1016/j.sbi.2019.01.004 -
Nutrients Jun 2018Cancer initiation and progression are the result of genetic and/or epigenetic alterations. Acetylation-mediated histone/non-histone protein modification plays an... (Review)
Review
Cancer initiation and progression are the result of genetic and/or epigenetic alterations. Acetylation-mediated histone/non-histone protein modification plays an important role in the epigenetic regulation of gene expression. Histone modification is controlled by the balance between histone acetyltransferase and (HAT) and histone deacetylase (HDAC) enzymes. Imbalance between the activities of these two enzymes is associated with various forms of cancer. Histone deacetylase inhibitors (HDACi) regulate the activity of HDACs and are being used in cancer treatment either alone or in combination with other chemotherapeutic drugs/radiotherapy. The Food and Drug Administration (FDA) has already approved four compounds, namely vorinostat, romidepsin, belinostat, and panobinostat, as HDACi for the treatment of cancer. Several other HDACi of natural and synthetic origin are under clinical trial for the evaluation of efficiency and side-effects. Natural compounds of plant, fungus, and actinomycetes origin, such as phenolics, polyketides, tetrapeptide, terpenoids, alkaloids, and hydoxamic acid, have been reported to show potential HDAC-inhibitory activity. Several HDACi of natural and dietary origin are butein, protocatechuic aldehyde, kaempferol (grapes, green tea, tomatoes, potatoes, and onions), resveratrol (grapes, red wine, blueberries and peanuts), sinapinic acid (wine and vinegar), diallyl disulfide (garlic), and zerumbone (ginger). HDACi exhibit their antitumor effect by the activation of cell cycle arrest, induction of apoptosis and autophagy, angiogenesis inhibition, increased reactive oxygen species generation causing oxidative stress, and mitotic cell death in cancer cells. This review summarizes the HDACs classification, their aberrant expression in cancerous tissue, structures, sources, and the anticancer mechanisms of HDACi, as well as HDACi that are either FDA-approved or under clinical trials.
Topics: Acetylation; Animals; Antineoplastic Agents; Drug Discovery; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Molecular Targeted Therapy; Mutation; Neoplasms; Substrate Specificity
PubMed: 29882797
DOI: 10.3390/nu10060731 -
International Journal of Medical... 2020Photoreceptors are critical components of the retina and play a role in the first step of the conversion of light to electrical signals. The differentiation and... (Review)
Review
Photoreceptors are critical components of the retina and play a role in the first step of the conversion of light to electrical signals. The differentiation and degeneration of photoreceptors are regulated by specific genes and proteins. With the development of epigenetic approaches, scientists have discovered that histone modifications, such as acetylation, methylation, ubiquitylation, and phosphorylation, may modulate the processes of photoreceptor differentiation and degeneration. Histone acetylation is regulated by two opposing classes of enzymes, namely, histone acetyltransferases (HATs) and histone deacetylases (HDACs), which add and remove acetyl groups to and from target histones, respectively, causing changes in transcriptional activity. Herein, we review the effects of HATs and HDACs on the differentiation and degeneration of photoreceptors and discuss the underlying mechanisms of these effects.
Topics: Acetylation; Animals; Histone Acetyltransferases; Histone Deacetylases; Histones; Humans; Phosphorylation; Photoreceptor Cells, Vertebrate
PubMed: 32624685
DOI: 10.7150/ijms.43140 -
Experimental Biology and Medicine... Jan 2021Cardiovascular diseases are the leading cause of mortality and morbidity worldwide. Histone deacetylases (HDACs) play an important role in the epigenetic regulation of... (Review)
Review
Cardiovascular diseases are the leading cause of mortality and morbidity worldwide. Histone deacetylases (HDACs) play an important role in the epigenetic regulation of genetic transcription in response to stress or pathological conditions. HDACs interact with a complex co-regulatory network of transcriptional regulators, deacetylate histones or non-histone proteins, and modulate gene expression in the heart. The selective HDAC inhibitors have been considered to be a critical target for the treatment of cardiac disease, especially for ameliorating cardiac dysfunction. In this review, we discuss our current knowledge of the cellular and molecular basis of HDACs in mediating cardiac development and hypertrophy and related pharmacologic interventions in heart disease.
Topics: Animals; Heart Diseases; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Small Molecule Libraries; Stem Cells; Translational Research, Biomedical
PubMed: 32727215
DOI: 10.1177/1535370220944128 -
Current Opinion in Structural Biology Dec 2011Metal-dependent histone deacetylases (HDACs) catalyze the hydrolysis of acetyl-L-lysine side chains in histone and nonhistone proteins to yield l-lysine and acetate.... (Review)
Review
Metal-dependent histone deacetylases (HDACs) catalyze the hydrolysis of acetyl-L-lysine side chains in histone and nonhistone proteins to yield l-lysine and acetate. This chemistry plays a critical role in the regulation of numerous biological processes. Aberrant HDAC activity is implicated in various diseases, and HDACs are validated targets for drug design. Two HDAC inhibitors are currently approved for cancer chemotherapy, and other inhibitors are in clinical trials. To date, X-ray crystal structures are available for four human HDACs (2, 4, 7, and 8) and three HDAC-related deacetylases from bacteria (histone deacetylase-like protein (HDLP); histone deacetylase-like amidohydrolase (HDAH); acetylpolyamine amidohydrolase (APAH)). Structural comparisons among these enzymes reveal a conserved constellation of active site residues, suggesting a common mechanism for the metal-dependent hydrolysis of acetylated substrates. Structural analyses of HDACs and HDAC-related deacetylases guide the design of tight-binding inhibitors, and future prospects for developing isozyme-specific inhibitors are quite promising.
Topics: Acetylation; Animals; Catalytic Domain; Crystallography, X-Ray; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Lysine; Metalloproteins; Protein Conformation
PubMed: 21872466
DOI: 10.1016/j.sbi.2011.08.004