scholarly journals Histone deacetylases as targets for treatment of multiple diseases

2013 ◽  
Vol 124 (11) ◽  
pp. 651-662 ◽  
Author(s):  
Jinhua Tang ◽  
Haidong Yan ◽  
Shougang Zhuang
Keyword(s):  
Histone Deacetylases ◽  
Metabolic Disorders ◽  
Interstitial Fibrosis ◽  
Inflammatory Diseases ◽  
Hdac Inhibitors ◽  
Cell Types ◽  
Immunomodulatory Activity ◽  
Anti Cancer ◽  
Proliferation And Differentiation ◽  
Autoimmune And Inflammatory Diseases

HDACs (histone deacetylases) are a group of enzymes that deacetylate histones as well as non-histone proteins. They are known as modulators of gene transcription and are associated with proliferation and differentiation of a variety of cell types and the pathogenesis of some diseases. Recently, HDACs have come to be considered crucial targets in various diseases, including cancer, interstitial fibrosis, autoimmune and inflammatory diseases, and metabolic disorders. Pharmacological inhibitors of HDACs have been used or tested to treat those diseases. In the present review, we will examine the application of HDAC inhibitors in a variety of diseases with the focus on their effects of anti-cancer, fibrosis, anti-inflammatory, immunomodulatory activity and regulating metabolic disorders.

scholarly journals Selective Targeting of Epigenetic Readers and Histone Deacetylases in Autoimmune and Inflammatory Diseases: Recent Advances and Future Perspectives

2021 ◽  
Vol 11 (5) ◽  
pp. 336
Author(s):  
Mohammed Ghiboub ◽  
Ahmed M. I. Elfiky ◽  
Menno P. J. de Winther ◽  
Nicola R. Harker ◽  
David F. Tough ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Inflammatory Diseases ◽  
Selective Inhibition ◽  
In Vivo Studies ◽  
Beneficial Effects ◽  
Domain Specific ◽  
Recent Advances ◽  
Autoimmune And Inflammatory Diseases

Histone deacetylases (HDACs) and bromodomain-containing proteins (BCPs) play a key role in chromatin remodeling. Based on their ability to regulate inducible gene expression in the context of inflammation and cancer, HDACs and BCPs have been the focus of drug discovery efforts, and numerous small-molecule inhibitors have been developed. However, dose-limiting toxicities of the first generation of inhibitors, which typically target multiple HDACs or BCPs, have limited translation to the clinic. Over the last decade, an increasing effort has been dedicated to designing class-, isoform-, or domain-specific HDAC or BCP inhibitors, as well as developing strategies for cell-specific targeted drug delivery. Selective inhibition of the epigenetic modulators is helping to elucidate the functions of individual epigenetic proteins and has the potential to yield better and safer therapeutic strategies. In accordance with this idea, several in vitro and in vivo studies have reported the ability of more selective HDAC/BCP inhibitors to recapitulate the beneficial effects of pan-inhibitors with less unwanted adverse events. In this review, we summarize the most recent advances with these strategies, discussing advantages and limitations of these approaches as well as some therapeutic perspectives, focusing on autoimmune and inflammatory diseases.

scholarly journals Identification of HDAC Inhibitors Using a Cell-Based HDAC I/II Assay

2016 ◽  
Vol 21 (6) ◽  
pp. 643-652 ◽  
Author(s):  
Chia-Wen Hsu ◽  
David Shou ◽  
Ruili Huang ◽  
Thai Khuc ◽  
Sheng Dai ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Histone Deacetylases ◽  
High Throughput Screening ◽  
Human Cancer ◽  
Hdac Inhibitors ◽  
Cell Types ◽  
Histone Deacetylation ◽  
Human Cancer Cell Lines ◽  
Human Neural Stem Cells

Histone deacetylases (HDACs) are a class of epigenetic enzymes that regulate gene expression by histone deacetylation. Altered HDAC function has been linked to cancer and neurodegenerative diseases, making HDACs popular therapeutic targets. In this study, we describe a screening approach for identification of compounds that inhibit endogenous class I and II HDACs. A homogeneous, luminogenic HDAC I/II assay was optimized in a 1536-well plate format in several human cancer cell lines, including HCT116 and human neural stem cells. The assay confirmed 37 known HDAC inhibitors from two libraries of known epigenetics-active compounds. Using the assay, we identified a group of potential HDAC inhibitors by screening the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection of 2527 small-molecule drugs. The selected compounds showed similar HDAC I/II inhibitory potency and efficacy values in both HCT116 and neural stem cells. Several previously unidentified HDAC inhibitors were further evaluated and profiled for their selectivity against a panel of 10 HDAC I/II isoforms using fluorogenic HDAC biochemical assays. In summary, our results show that several novel HDAC inhibitors, including nafamostat and piceatannol, have been identified using the HDAC I/II cell-based assay, and multiple cell types have been validated for high-throughput screening of large chemical libraries.

scholarly journals Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective

Metabolites ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 792
Author(s):  
Jacob King ◽  
Maya Patel ◽  
Sriram Chandrasekaran
Keyword(s):  
Systems Biology ◽  
Histone Deacetylases ◽  
Metabolic Disorders ◽  
Viral Infections ◽  
Hdac Inhibitors ◽  
Cancer Cell Line ◽  
Biological Processes ◽  
Single Cell Sequencing ◽  
Future Potential ◽  
Metabolic Biomarkers

Histone deacetylases (HDACs) are epigenetic enzymes that play a central role in gene regulation and are sensitive to the metabolic state of the cell. The cross talk between metabolism and histone acetylation impacts numerous biological processes including development and immune function. HDAC inhibitors are being explored for treating cancers, viral infections, inflammation, neurodegenerative diseases, and metabolic disorders. However, how HDAC inhibitors impact cellular metabolism and how metabolism influences their potency is unclear. Discussed herein are recent applications and future potential of systems biology methods such as high throughput drug screens, cancer cell line profiling, single cell sequencing, proteomics, metabolomics, and computational modeling to uncover the interplay between metabolism, HDACs, and HDAC inhibitors. The synthesis of new systems technologies can ultimately help identify epigenomic and metabolic biomarkers for patient stratification and the design of effective therapeutics.

Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs

2019 ◽  
Vol 11 (477) ◽  
pp. eaat9143 ◽  
Author(s):  
Susannah L. Hewitt ◽  
Ailin Bai ◽  
Dyane Bailey ◽  
Kana Ichikawa ◽  
John Zielinski ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Complete Response ◽  
Cell Types ◽  
Immunomodulatory Activity ◽  
Messenger Rnas ◽  
Tumor Microenvironments ◽  
Microbial Invasion

Many solid cancers contain dysfunctional immune microenvironments. Immune system modulators that initiate responses to foreign pathogens could be promising candidates for reigniting productive responses toward tumors. Interleukin-1 (IL-1) and IL-12 cytokine family members cooperate at barrier tissues after microbial invasion, in human inflammatory diseases, and in antitumoral immunity. IL-36γ, in classic alarmin fashion, acts in damaged tissues, whereas IL-23 centrally coordinates immune responses to danger signals. In this study, direct intratumoral delivery of messenger RNAs (mRNAs) encoding these cytokines produced robust anticancer responses in a broad range of tumor microenvironments. The addition of mRNA encoding the T cell costimulator OX40L increased complete response rates in treated and untreated distal tumors compared to the cytokine mRNAs alone. Mice exhibiting complete responses were subsequently protected from tumor rechallenge. Treatments with these mRNA mixtures induced downstream cytokine and chemokine expression, and also activated multiple dendritic cell (DC) and T cell types. Consistent with this, efficacy was dependent on Batf3-dependent cross-presenting DCs and cytotoxic CD8+T cells. IL-23/IL-36γ/OX40L triplet mRNA mixture triggered substantial immune cell recruitment into tumors, enabling effective tumor destruction irrespective of previous tumoral immune infiltrates. Last, combining triplet mRNA with checkpoint blockade led to efficacy in models otherwise resistant to systemic immune checkpoint inhibition. Human cell studies showed similar cytokine responses to the individual components of this mRNA mixture, suggesting translatability of immunomodulatory activity to human patients.

The role of histone deacetylases in rheumatoid arthritis fibroblast-like synoviocytes

2013 ◽  
Vol 41 (3) ◽  
pp. 783-788 ◽  
Author(s):  
Sarah Hawtree ◽  
Munitta Muthana ◽  
Anthony G. Wilson
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Cell Types ◽  
Epigenetic Mark ◽  
Aggressive Phenotype ◽  
Fibroblast Like Synoviocytes

RA (rheumatoid arthritis) is an inflammatory disease of synovial joints affecting approximately 1% of the population. One of the main cell types involved in damage to RA joint tissue is the FLSs (fibroblast-like synoviocytes). These have a semi-transformed, auto-aggressive phenotype typified by loss of contact inhibition, reduced apoptosis and the production of matrix-degrading enzymes. The mechanisms involved in the development of this phenotype are unclear; however, increasing evidence implicates alterations in the epigenetic regulation of gene expression. Reduced acetylation of amino acids in the tails of histone proteins is an epigenetic mark associated with transcriptional repression and is controlled by the HDAC (histone deacetylase) enzyme family. To date, evidence has implicated HDACs in the auto-aggressive phenotype of FLSs, and administration of HDAC inhibitors to both animal models of RA and individuals with juvenile arthritis has shown efficacy in attenuating inflammation and tissue damage. This highlights a role for HDACs in disease pathogenesis and, more importantly, that HDACs are potential novel therapeutic targets.

scholarly journals Targeting HDAC Complexes in Asthma and COPD

Epigenomes ◽  
2019 ◽  
Vol 3 (3) ◽  
pp. 19 ◽  
Author(s):  
Martijn R. H. Zwinderman ◽  
Sander de Weerd ◽  
Frank J. Dekker
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Intracellular Signaling ◽  
Histone Deacetylases ◽  
Inflammatory Diseases ◽  
Hdac Inhibitors ◽  
Chronic Obstructive ◽  
Protein Acetylation ◽  
Obstructive Pulmonary Disease ◽  
Intracellular Signaling Pathways ◽  
Clinical Models

Around three million patients die due to airway inflammatory diseases each year. The most notable of these diseases are asthma and chronic obstructive pulmonary disease (COPD). Therefore, new therapies are urgently needed. Promising targets are histone deacetylases (HDACs), since they regulate posttranslational protein acetylation. Over a thousand proteins are reversibly acetylated, and acetylation critically influences aberrant intracellular signaling pathways in asthma and COPD. The diverse set of selective and non-selective HDAC inhibitors used in pre-clinical models of airway inflammation show promising results, but several challenges still need to be overcome. One such challenge is the design of HDAC inhibitors with unique selectivity profiles, such as selectivity towards specific HDAC complexes. Novel strategies to disrupt HDAC complexes should be developed to validate HDACs further as targets for new anti-inflammatory pulmonary treatments.

Development of an Efficient Screening System for HDAC Inhibitor Based on TCF Response Element

2019 ◽  
Vol 18 (15) ◽  
pp. 2131-2136
Author(s):  
Chen Pang ◽  
Limeng Dai ◽  
Gang He ◽  
You Lu ◽  
Bo Zhang
Keyword(s):  
Natural Products ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Screening System ◽  
Chemical Libraries ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Core Histones ◽  
Drug Treatments ◽  
Efficient Screening

Background: Acetylation of core histones is governed by opposing actions of a variety of histone acetyltransferases (HATs) and Histone Deacetylases (HDACs). Deregulation of histone acetylation has been causally linked to cancer development and progression, and can be potentially reversed by drug treatments. HDAC inhibitors (HDACis) have the anti-cancer effects such as induction of cell cycle arrest, promotion of cell apoptosis, and inhibition of metastasis. Many of these HDACis are currently in clinical development. Methods: To screen for novel compound with HDACis activity, cell-based strategy has been developed in current work. The interaction of HDACs and TCFs was determined by reporter assay, and Natural products library (A10) was screened by our system in colon cancer cells. Results: Based on the interaction of HDACs and TCFs, compounds with HDACis activity could be easily picked out from Natural products library (A10) by using this screening system. Finally, a compound Wsu-18 was preliminarily identified as a potential HDACis. Conclusion: These data suggest our screening system for HDACis was efficient and promising, and it is suitable for screening other small molecular chemical libraries.

scholarly journals Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 556 ◽  
Author(s):  
Giorgio Milazzo ◽  
Daniele Mercatelli ◽  
Giulia Di Muzio ◽  
Luca Triboli ◽  
Piergiuseppe De Rosa ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Histone Deacetylases ◽  
Expression Profiles ◽  
Hdac Inhibitors ◽  
Gene Expression Profiles ◽  
Chromatin Binding ◽  
Human Interactome ◽  
Anti Cancer ◽  
Functional Consequences

Histone deacetylases (HDACs) are evolutionary conserved enzymes which operate by removing acetyl groups from histones and other protein regulatory factors, with functional consequences on chromatin remodeling and gene expression profiles. We provide here a review on the recent knowledge accrued on the zinc-dependent HDAC protein family across different species, tissues, and human pathologies, specifically focusing on the role of HDAC inhibitors as anti-cancer agents. We will investigate the chemical specificity of different HDACs and discuss their role in the human interactome as members of chromatin-binding and regulatory complexes.

scholarly journals FcεRI-HDAC3-MCP1 Signaling Axis Promotes Passive Anaphylaxis Mediated by Cellular Interactions

2019 ◽  
Vol 20 (19) ◽  
pp. 4964
Author(s):  
Kim ◽  
Kwon ◽  
Jung ◽  
Kim ◽  
Jeoung
Keyword(s):  
Mast Cells ◽  
Histone Deacetylases ◽  
Immunoglobulin E ◽  
Inflammatory Diseases ◽  
Hdac Inhibitors ◽  
Systemic Reaction ◽  
Allergic Diseases ◽  
Cellular Interactions ◽  
Signaling Axis ◽  
Life Threatening

Anaphylaxis is an acute and life-threatening systemic reaction. Food, drug, aero-allergen and insect sting are known to induce anaphylaxis. Mast cells and basophils are known to mediate Immunoglobulin E (IgE)-dependent anaphylaxis, while macrophages, neutrophils and basophils mediate non IgE-dependent anaphylaxis. Histone deacetylases (HDACs) play various roles in biological processes by deacetylating histones and non-histones proteins. HDAC inhibitors can increase the acetylation of target proteins and affect various inflammatory diseases such as cancers and allergic diseases. HDAC3, a class I HDAC, is known to act as epigenetic and transcriptional regulators. It has been shown that HDAC3 can interact with the high-affinity Immunoglobulin E receptor (FcεRI), to mediate passive anaphylaxis and cellular interactions during passive anaphylaxis. Effects of HDAC3 on anaphylaxis, cellular interactions involving mast cells and macrophages during anaphylaxis, and any tumorigenic potential of cancer cells enhanced by mast cells will be discussed in this review. Roles of microRNAs that form negative feedback loops with hallmarks of anaphylaxis such as HDAC3 in anaphylaxis and cellular interactions will also be discussed. The roles of MCP1 regulated by HDAC3 in cellular interactions during anaphylaxis are discussed. Roles of exosomes in cellular interactions mediated by HDAC3 during anaphylaxis are also discussed. Thus, review might provide clues for development of drugs targeting passive anaphylaxis.

scholarly journals Minireview: Glucocorticoids in Autoimmunity: Unexpected Targets and Mechanisms

2011 ◽  
Vol 25 (7) ◽  
pp. 1075-1086 ◽  
Author(s):  
Jamie R. Flammer ◽  
Inez Rogatsky
Keyword(s):  
Antiinflammatory Activity ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Cytokine Gene Expression ◽  
Extensive Literature ◽  
Complex Functions ◽  
Numerous Cell ◽  
Autoimmune And Inflammatory Diseases ◽  
Health And Disease ◽  
Synthetic Glucocorticoids

Abstract For decades, natural and synthetic glucocorticoids (GC) have been among the most commonly prescribed classes of immunomodulatory drugs. Their unsurpassed immunosuppressive and antiinflammatory activity along with cost-effectiveness makes these compounds a treatment of choice for the majority of autoimmune and inflammatory diseases, despite serious side effects that frequently accompany GC therapy. The activated GC receptor (GR) that conveys the signaling information of these steroid ligands to the transcriptional machinery engages a number of pathways to ultimately suppress autoimmune responses. Of those, GR-mediated apoptosis of numerous cell types of hematopoietic origin and suppression of proinflammatory cytokine gene expression have been described as the primary mechanisms responsible for the antiinflammatory actions of GC. However, along with the ever-increasing appreciation of the complex functions of the immune system in health and disease, we are beginning to recognize new facets of GR actions in immune cells. Here, we give a brief overview of the extensive literature on the antiinflammatory activities of GC and discuss in greater detail the unexpected pathways, factors, and mechanisms that have recently begun to emerge as novel targets for GC-mediated immunosuppression.

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