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Targeting Histone Deacetylases with Natural and Synthetic Agents: an Emerging Anticancer Strategy

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Targeting Histone Deacetylases with Natural and Synthetic Agents: an Emerging Anticancer Strategy nutrients Review Targeting Histone Deacetylases with Natural and Synthetic Agents: An Emerging Anticancer Strategy Amit Kumar Singh 1 ID , Anupam Bishayee 2 ID and Abhay K. Pandey 1,* ID 1 Department of Biochemistry, University of Allahabad, Allahabad 211 002, Uttar Pradesh, India; [email protected] 2 Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA; [email protected] or [email protected] * Correspondence: [email protected]; Tel.: +91-983-952-1138 Received: 7 May 2018; Accepted: 4 June 2018; Published: 6 June 2018 Abstract: 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. Keywords: cancer; histone deacetylases; histone deacetylase inhibitors; vorinostat; natural HDACi; apoptosis 1. Introduction Cancer is the second leading cause of death worldwide and caused 8.8 million deaths in 2015. Globally, 1 out of 6 deaths is because of cancer. Low and middle-income countries are the hotspot of cancer deaths, accounting for approximately 70% of deaths. Lung cancer is the most common cause of cancer death worldwide. According to the National Center for Health Statistics about 1.73 million new cancer cases and 0.6 million cancer deaths are projected to occur in the United States in 2018 [1]. Cancer results from altered cell physiology leading to self-sufficient growth potential, loss of cell cycle control, extended angiogenesis, delay in replicative senescence, dysregulated apoptosis, invasion, and metastasis [2,3]. Progression of the disease is not only governed by genomic and genetic changes, such as translocation, amplification, deletion and point mutation, it also involves epigenetic Nutrients 2018, 10, 731; doi:10.3390/nu10060731 www.mdpi.com/journal/nutrients Nutrients 2018, 10, x 731 FOR PEER REVIEW 2 of 32 31 changes, such as translocation, amplification, deletion and point mutation, it also involves epigenetic changeschanges;; i.e.,i.e., alteration alteration in in the the pattern pattern of gene of expressiongene expression without without changing changing underlying underlying DNA sequence. DNA sequence.Methylation Methylation of DNA, histone of DNA, protein histone modifications protein modifications and non-coding and RNA-mediatednon-coding RNA gene-mediated silencing gene are silencingthe major are epigenetic the major changes, epigenetic reversible changes, in naturereversible [4]. in nature [4]. Chromatin is a compact and highly ordered ordered structur structuree comprised comprised of of DNA DNA and and histone histone protein. protein. Nucleosome, the basic unit of chromatin, is made up of 147 bp of DNA superhelix wrapped around histone core protein containing two two copies each each of of H2A, H2A, H2B, H2B, H3 H3 and and H4. H4. H1 H1 is is the the linker linker histone. histone. The core playsplays anan importantimportant role role in in establishing establishing interactions interactions between between the the nucleosomes nucleosomes and and within within the thenucleosome nucleosome particle particle itself. itself. N-terminals N-terminals (histone (histone tails) of coretails) histones of core are histones flexible andare unstructuredflexible and unstructuredwhile the rest while of histone the rest proteins of histone are proteins basically are globular basically andglobular highly and ordered. highly ordere Dependingd. Depending on the onepigenetic the epigenetic changes inchanges histone in tail, histone chromatin tail, undergoeschromatin variousundergoes conformational various conformational changes responsible changes for responsibleupregulation orfor downregulation upregulation ofor respective downregulation genes [5, 6].of The respective common posttranslationalgenes [5,6]. The modifications common posttranslationaloccurring in histones modifications are acetylation, occurring methylation, in histones phosphorylation, are acetylation, sumoylation,methylation, phosphorylation, ubiquitinylation, sumoylation,and ADP ribosylation. ubiquitinylation, and ADP ribosylation. Acetylation of a lysine residue of histone was discovered by Vincent Allfrey and colleagues in 1964 andand basedbased on on the the finding finding it has it has been been proposed proposed that acetylationthat acetylation of "-amino of ε- groupamino ofgroup lysine of residues lysine residuescould play could a role play in gene a role expression in gene expression [7,8]. Acetylation [7,8]. Acetylation and deacetylation and deacetylation of N-terminal of "N-amino-terminal group ε- aminoof lysine group residues of lysine are regulated residues by are two regulated enzymes, by namely two enzymes, histone acetyltransferase namely histone (HAT) acetyltransferase and histone (HAT)deacetylase and histone (HDAC) deacetylase (Figure1). Acetylation(HDAC) (Figure neutralizes 1). Acetylation the positive neutralizes charge and the decreases positive charge the affinity and decreasesbetween the the histone affinity and between DNA helixthe histone responsible and DNA for relaxation helix responsible of conformation for relaxation and greater of conformation accessibility andto transcription greater accessibility machinery to [4 ,9transcription]. Therefore, acetylationmachinery is[4,9] generally. Therefore, associated acetylation with gene is activation,generally ashowever,sociated deacetylation with gene activation, catalyzed byhowever, HDAC inducesdeacetylation chromatin catalyzed condensation by HDAC and induces downregulation chromatin of condensationgene expression. and N-terminal downregulation acetylation of gene of lysineexpression. residue N also-terminal occurs acetylation in non-histone of lysine proteins, residue such also as occurscytoplasmic in non proteins,-histone transcriptionproteins, such factors as cytoplasmic responsible proteins, for alteration transcription in gene factors expression responsible and other for alterationcellular processes in gene expression [10]. and other cellular processes [10]. Figure 1. HistoneHistone acetylation acetylation at at the the N N-terminus-terminus lysine lysine by by histone histone acetyltransferases acetyltransferases (HATs) (HATs) and deacetylation by histone deacetylases (HDACs). Imbalance in the activities of enzymes HATs and HDACs is responsible for the development Imbalance in the activities of enzymes HATs and HDACs is responsible for the development and and progression of wide variety of cancers [2]. Histone deacetylase inhibitors (HDACi) increase the progression of wide variety of cancers [2]. Histone deacetylase inhibitors (HDACi) increase the level of level of acetylated lysine residues of core histone which in turn restarts the expression of silenced acetylated lysine residues of core histone which in turn restarts the expression of silenced regulatory regulatory genes in the cancerous cell and therefore, HDACi are now emerging as anticancer agents genes in the cancerous cell and therefore, HDACi are now emerging as anticancer agents [11]. [11]. Epidemiological studies have suggested that vegetables, fruits, whole grains, microorganism- Epidemiological studies have suggested that vegetables, fruits, whole grains, microorganism- derived bioactive components, and fatty acids provide protection against some forms of cancer and derived bioactive components, and fatty acids provide protection against some forms of cancer and other diseases without detectable side effects [12–14]. Many dietary compounds that have been other diseases without detectable side effects [12–14]. Many dietary compounds that have been identified as having HDAC-inhibitory activities implicated in therapeutic potential in the context of identified as having HDAC-inhibitory activities implicated in therapeutic potential
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