Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of transcription factors which can induce or repress gene transcription. The HATs catalyze acetylation and the events related to gene transcription and are also responsible for transporting newly synthesized histones from the cytoplasm to the nucleus. The activity of HDACs is mainly involved in silencing gene expression and according to their specialized functions are divided into classes I, II, III and IV. The disturbance of the expression and mutations of HDAC genes causes the aberrant transcription of key genes regulating important cancer pathways such as cell proliferation, cell-cycle regulation and apoptosis. In view of their role in cancer pathways, HDACs are considered promising therapeutic targets and the development of HDAC inhibitors is a hot topic in the search for new anticancer drugs. The present review will focus on HDACs I, II and IV, the best known inhibitors and potential alternative inhibitors derived from natural and synthetic products which can be used to influence HDAC activity and the development of new cancer therapies.

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Food Bioactive HDAC Inhibitors in the Epigenetic Regulation of Heart Failure

Nutrients ◽

10.3390/nu10081120 ◽

2018 ◽

Vol 10 (8) ◽

pp. 1120 ◽

Cited By ~ 8

Author(s):

Levi Evans ◽

Bradley Ferguson

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Histone Deacetylases ◽

Regulation Of Gene Expression ◽

Hdac Inhibitors ◽

Drug Efficacy ◽

Histone Deacetylation ◽

Epigenetic Modifiers

Approximately 5.7 million U.S. adults have been diagnosed with heart failure (HF). More concerning is that one in nine U.S. deaths included HF as a contributing cause. Current HF drugs (e.g., β-blockers, ACEi) target intracellular signaling cascades downstream of cell surface receptors to prevent cardiac pump dysfunction. However, these drugs fail to target other redundant intracellular signaling pathways and, therefore, limit drug efficacy. As such, it has been postulated that compounds designed to target shared downstream mediators of these signaling pathways would be more efficacious for the treatment of HF. Histone deacetylation has been linked as a key pathogenetic element for the development of HF. Lysine residues undergo diverse and reversible post-translational modifications that include acetylation and have historically been studied as epigenetic modifiers of histone tails within chromatin that provide an important mechanism for regulating gene expression. Of recent, bioactive compounds within our diet have been linked to the regulation of gene expression, in part, through regulation of the epi-genome. It has been reported that food bioactives regulate histone acetylation via direct regulation of writer (histone acetyl transferases, HATs) and eraser (histone deacetylases, HDACs) proteins. Therefore, bioactive food compounds offer unique therapeutic strategies as epigenetic modifiers of heart failure. This review will highlight food bio-actives as modifiers of histone deacetylase activity in the heart.

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Zinc Dependent Histone Deacetylase Inhibitors in Cancer Therapeutics: Recent Update

Current Medicinal Chemistry ◽

10.2174/0929867325666180530094120 ◽

2020 ◽

Vol 26 (40) ◽

pp. 7212-7280 ◽

Cited By ~ 4

Author(s):

Faria Sultana ◽

Kesari Lakshmi Manasa ◽

Siddiq Pasha Shaik ◽

Srinivasa Reddy Bonam ◽

Ahmed Kamal

Keyword(s):

Gene Expression ◽

Drug Therapy ◽

Histone Deacetylases ◽

Histone Deacetylase Inhibitors ◽

Regulation Of Gene Expression ◽

Hdac Inhibitors ◽

Cancer Therapeutics ◽

Rational Drug Design ◽

Combination Drug Therapy ◽

Combination Drug

Background: Histone deacetylases (HDAC) are an important class of enzymes that play a pivotal role in epigenetic regulation of gene expression that modifies the terminal of core histones leading to remodelling of chromatin topology and thereby controlling gene expression. HDAC inhibitors (HDACi) counter this action and can result in hyperacetylation of histones, thereby inducing an array of cellular consequences such as activation of apoptotic pathways, generation of reactive oxygen species (ROS), cell cycle arrest and autophagy. Hence, there is a growing interest in the potential clinical use of HDAC inhibitors as a new class of targeted cancer therapeutics. Methodology and Result: Several research articles spanning between 2016 and 2017 were reviewed in this article and presently offer critical insights into the important strategies such as structure-based rational drug design, multi-parameter lead optimization methodologies, relevant SAR studies and biology of various class of HDAC inhibitors, such as hydroxamic acids, benzamides, cyclic peptides, aliphatic acids, summarising the clinical trials and results of various combination drug therapy till date. Conclusion: This review will provide a platform to the synthetic chemists and biologists to cater the needs of both molecular targeted therapy and combination drug therapy to design and synthesize safe and selective HDAC inhibitors in cancer therapeutics.

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Histone deacetylases (HDACs): characterization of the classical HDAC family

Biochemical Journal ◽

10.1042/bj20021321 ◽

2003 ◽

Vol 370 (3) ◽

pp. 737-749 ◽

Cited By ~ 1884

Author(s):

Annemieke J.M. de RUIJTER ◽

Albert H. van GENNIP ◽

Huib N. CARON ◽

Stephan KEMP ◽

André B.P. van KUILENBURG

Keyword(s):

Gene Expression ◽

Histone Deacetylases ◽

Regulation Of Gene Expression ◽

Hdac Inhibitors ◽

Building Blocks ◽

Post Translational Modification ◽

Comprehensive Overview ◽

Almost All ◽

Enzyme Complexes

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.

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In Search of Selectivity: Design, Synthesis, and Biological Evaluation of New Classes of HDAC Inhibitors

Proceedings ◽

10.3390/proceedings2019022063 ◽

2019 ◽

Vol 22 (1) ◽

pp. 63

Author(s):

L. M. Viranga Tillekeratne ◽

Ayad Ayad Al-Hamashi ◽

Samkeliso Dlamini ◽

William Taylor ◽

Radhika Koranne ◽

...

Keyword(s):

Gene Expression ◽

Dna Sequences ◽

Metal Binding ◽

Histone Deacetylases ◽

Regulation Of Gene Expression ◽

Hdac Inhibitors ◽

Biological Evaluation ◽

Design Synthesis ◽

Design And Synthesis ◽

Epigenetic Modulation

Epigenetic regulation of gene expression without changing DNA sequences is a promising strategy in developing therapeutic agents for human diseases, especially cancer. Histone deacetylases (HDACs) are a family of enzymes involved in epigenetic modulation of gene expression by chromatin remodeling. Deacetylation of the lysine side chains of histones by HDAC proteins renders DNA transcriptionally inactive, resulting in the inhibition of expression of tumor suppressor genes, leading to tumorigenesis and tumor progression. Therefore, inhibiting HDAC enzymes has become an attractive strategy to modulate gene expression as a strategy for developing anticancer drugs. There are currently four FDA-approved cancer drugs in clinical use, and many more are in different stages of clinical trials. However, their clinical utility is limited due to undesirable side effects, mainly attributed to their lack of selectivity and the presence of a hydroxamic acid moiety as the metal-binding group. There are eighteen different isoforms of HDACs belonging to four classes that have been identified in humans. A major challenge in HDAC inhibitor development is how to make them selective for these HDAC isoforms and classes. We report the design and synthesis of new classes of HDAC inhibitors and the evaluation of their anticancer activity and selectivity.

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Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention

Pharmaceutics ◽

10.3390/pharmaceutics14010209 ◽

2022 ◽

Vol 14 (1) ◽

pp. 209

Author(s):

Dusan Ruzic ◽

Nemanja Djoković ◽

Tatjana Srdić-Rajić ◽

Cesar Echeverria ◽

Katarina Nikolic ◽

...

Keyword(s):

Gene Expression ◽

Small Molecules ◽

Histone Deacetylases ◽

Hdac Inhibitors ◽

Critical Event ◽

Cancer Therapies ◽

Epigenetic Alterations ◽

Histone Hyperacetylation ◽

Current Therapies

The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.

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Computational QSAR model combined molecular descriptors and fingerprints to predict HDAC1 inhibitors

médecine/sciences ◽

10.1051/medsci/201834f110 ◽

2018 ◽

Vol 34 ◽

pp. 52-58 ◽

Cited By ~ 3

Author(s):

Jingsheng Shi ◽

Guanglei Zhao ◽

Yibing Wei

Keyword(s):

Histone Deacetylases ◽

Computational Models ◽

Nearest Neighbor ◽

Dynamic Balance ◽

Regulation Of Gene Expression ◽

Hdac Inhibitors ◽

Qsar Model ◽

Support Vector ◽

C4.5 Decision Tree ◽

Fold Cross Validation

The dynamic balance between acetylation and deacetylation of histones plays a crucial role in the epigenetic regulation of gene expression. It is equilibrated by two families of enzymes: histone acetyltransferases and histone deacetylases (HDACs). HDACs repress transcription by regulating the conformation of the higher-order chromatin structure. HDAC inhibitors have recently become a class of chemical agents for potential treatment of the abnormal chromatin remodeling process involved in certain cancers. In this study, we constructed a large dataset to predict the activity value of HDAC1 inhibitors. Each compound was represented with seven fingerprints, and computational models were subsequently developed to predict HDAC1 inhibitors via five machine learning methods. These methods include naïve Bayes, κ-nearest neighbor, C4.5 decision tree, random forest, and support vector machine (SVM) algorithms. The best predicting model was CDK fingerprint with SVM, which exhibited an accuracy of 0.89. This model also performed best in five-fold cross-validation. Some representative substructure alerts responsible for HDAC1 inhibitors were identified by using MoSS in KNIME, which could facilitate the identification of HDAC1 inhibitors.

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Histone deacetylase inhibitors and their potential role in inflammatory bowel diseases

Biochemical Society Transactions ◽

10.1042/bst0391092 ◽

2011 ◽

Vol 39 (4) ◽

pp. 1092-1095 ◽

Cited By ~ 19

Author(s):

Alexander J.P. Edwards ◽

Sylvia L.F. Pender

Keyword(s):

Gene Transcription ◽

Inflammatory Bowel Diseases ◽

Histone Deacetylases ◽

Histone Deacetylase Inhibitors ◽

T Regulatory Cells ◽

Hdac Inhibitors ◽

Novel Treatments ◽

Bowel Diseases ◽

Normal Gene ◽

Inflammatory Bowel

IBDs (inflammatory bowel diseases) are lifelong manifestations that significantly impair the quality of life of those who suffer from them. Although many therapies are now available, including immunomodulatory drugs such as Infliximab which have efficacy in IBD, not all patients respond and some patients generate autoantibodies against these drugs. Hence the search for novel treatments is ongoing. HDACs (histone deacetylases) are responsible for condensation of chromatin in the nucleus of cells and inhibition of gene transcription and are often dysregulated during cancer. HDAC inhibitors allow normal gene transcription to be restored and provide attractive therapeutic options, as they have been shown to be anti-inflammatory and anti-proliferative in cancer. Indeed, two HDAC inhibitors have been recently approved for the treatment of cutaneous T-cell lymphoma in the U.S.A. Recent research using animal models has shown that HDAC inhibitors may have a beneficial effect in colitis by boosting levels of Foxp3+ (forkhead box P3+) T-regulatory cells that dampen inflammation. In the present paper, we outline the background to IBD, HDACs and their inhibitors as well as discussing their current use in models of IBD.

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Epigenetic Research in Stem Cell Bioengineering—Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials

Cancers ◽

10.3390/cancers12041016 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1016 ◽

Cited By ~ 1

Author(s):

Claudia Dompe ◽

Krzysztof Janowicz ◽

Greg Hutchings ◽

Lisa Moncrieff ◽

Maurycy Jankowski ◽

...

Keyword(s):

Gene Expression ◽

Clinical Trials ◽

Stem Cell ◽

Cancer Therapy ◽

Regulation Of Gene Expression ◽

Epigenetic Modifications ◽

Transcriptional Level ◽

Cancer Therapies ◽

Stem Cell Engineering ◽

Anti Cancer

The epigenome denotes all the information related to gene expression that is not contained in the DNA sequence but rather results from chemical changes to histones and DNA. Epigenetic modifications act in a cooperative way towards the regulation of gene expression, working at the transcriptional or post-transcriptional level, and play a key role in the determination of phenotypic variations in cells containing the same genotype. Epigenetic modifications are important considerations in relation to anti-cancer therapy and regenerative/reconstructive medicine. Moreover, a range of clinical trials have been performed, exploiting the potential of epigenetics in stem cell engineering towards application in disease treatments and diagnostics. Epigenetic studies will most likely be the basis of future cancer therapies, as epigenetic modifications play major roles in tumour formation, malignancy and metastasis. In fact, a large number of currently designed or tested clinical approaches, based on compounds regulating epigenetic pathways in various types of tumours, employ these mechanisms in stem cell bioengineering.

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The Crosstalk between Acetylation and Phosphorylation: Emerging New Roles for HDAC Inhibitors in the Heart

International Journal of Molecular Sciences ◽

10.3390/ijms20010102 ◽

2018 ◽

Vol 20 (1) ◽

pp. 102 ◽

Cited By ~ 9

Author(s):

Justine Habibian ◽

Bradley Ferguson

Keyword(s):

Gene Expression ◽

Protein Phosphorylation ◽

Cross Talk ◽

Electrostatic Interactions ◽

Regulation Of Gene Expression ◽

Hdac Inhibitors ◽

Protein Activity ◽

Histone Protein ◽

Signal Transduction Protein ◽

And Function

Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical animal models of HF have highlighted histone deacetylase (HDAC) inhibitors as efficacious therapeutics that can stop and potentially reverse cardiac remodeling and dysfunction linked with HF development. HDACs remove acetyl groups from nucleosomal histones, altering DNA-histone protein electrostatic interactions in the regulation of gene expression. However, HDACs also remove acetyl groups from non-histone proteins in various tissues. Changes in histone and non-histone protein acetylation plays a key role in protein structure and function that can alter other post translational modifications (PTMs), including protein phosphorylation. Protein phosphorylation is a well described PTM that is important for cardiac signal transduction, protein activity and gene expression, yet the functional role for acetylation-phosphorylation cross-talk in the myocardium remains less clear. This review will focus on the regulation and function for acetylation-phosphorylation cross-talk in the heart, with a focus on the role for HDACs and HDAC inhibitors as regulators of acetyl-phosphorylation cross-talk in the control of cardiac function.

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Pbx1 Represses Osteoblastogenesis by Blocking Hoxa10-Mediated Recruitment of Chromatin Remodeling Factors

Molecular and Cellular Biology ◽

10.1128/mcb.00889-09 ◽

2010 ◽

Vol 30 (14) ◽

pp. 3531-3541 ◽

Cited By ~ 41

Author(s):

Jonathan A. R. Gordon ◽

Mohammad Q. Hassan ◽

Sharanjot Saini ◽

Martin Montecino ◽

Andre J. van Wijnen ◽

...

Keyword(s):

Gene Expression ◽

Histone Deacetylases ◽

Skeletal Development ◽

Regulation Of Gene Expression ◽

Gene Activation ◽

Gene Promoters ◽

Homeodomain Proteins ◽

Temporal Regulation ◽

Multipotent Cells ◽

P300 Recruitment

ABSTRACT Abdominal-class homeodomain-containing (Hox) factors form multimeric complexes with TALE-class homeodomain proteins (Pbx, Meis) to regulate tissue morphogenesis and skeletal development. Here we have established that Pbx1 negatively regulates Hoxa10-mediated gene transcription in mesenchymal cells and identified components of a Pbx1 complex associated with genes in osteoblasts. Expression of Pbx1 impaired osteogenic commitment of C3H10T1/2 multipotent cells and differentiation of MC3T3-E1 preosteoblasts. Conversely, targeted depletion of Pbx1 by short hairpin RNA (shRNA) increased expression of osteoblast-related genes. Studies using wild-type and mutated osteocalcin and Bsp promoters revealed that Pbx1 acts through a Pbx-binding site that is required to attenuate gene activation by Hoxa10. Chromatin-associated Pbx1 and Hoxa10 were present at osteoblast-related gene promoters preceding gene expression, but only Hoxa10 was associated with these promoters during transcription. Our results show that Pbx1 is associated with histone deacetylases normally linked with chromatin inactivation. Loss of Pbx1 from osteoblast promoters in differentiated osteoblasts was associated with increased histone acetylation and CBP/p300 recruitment, as well as decreased H3K9 methylation. We propose that Pbx1 plays a central role in attenuating the ability of Hoxa10 to activate osteoblast-related genes in order to establish temporal regulation of gene expression during osteogenesis.

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