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

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          Abstract

          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.

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          A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug-Repurposing

          David E Gordon, Gwendolyn M Jang, Mehdi Bouhaddou … (2020)
          SUMMARY The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
          Article 0 comments Cited 2314 times – based on 0 reviews     Review now
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            The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men.

            Xiang-Jiao Yang, Edward Seto (2008)
            Protein lysine deacetylases have a pivotal role in numerous biological processes and can be divided into the Rpd3/Hda1 and sirtuin families, each having members in diverse organisms including prokaryotes. In vertebrates, the Rpd3/Hda1 family contains 11 members, traditionally referred to as histone deacetylases (HDAC) 1-11, which are further grouped into classes I, II and IV. Whereas most class I HDACs are subunits of multiprotein nuclear complexes that are crucial for transcriptional repression and epigenetic landscaping, class II members regulate cytoplasmic processes or function as signal transducers that shuttle between the cytoplasm and the nucleus. Little is known about class IV HDAC11, although its evolutionary conservation implies a fundamental role in various organisms.
            Article 0 comments Cited 356 times – based on 0 reviews     Review now
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              Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials

              Yuan Sheng Cheng, Cai He, Manni Wang … (2019)
              Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. In this review, we summarize the aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.
              Article 0 comments Cited 311 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Genes (Basel)
                Journal ID (iso-abbrev): Genes (Basel)
                Journal ID (publisher-id): genes
                Title: Genes
                Publisher: MDPI
                ISSN (Electronic): 2073-4425
                Publication date (Electronic): 15 May 2020
                Publication date Collection: May 2020
                Volume: 11
                Issue: 5
                Electronic Location Identifier: 556
                Affiliations
                Department of Pharmacy and Biotechnology, University of Bologna, Via Selmi 3, 41026 Bologna, Italy; giorgio.milazzo@ 123456unibo.it (G.M.); danielemercatelli@ 123456gmail.com (D.M.); giulia.dimuzio@ 123456studio.unibo.it (G.D.M.); luca.triboli@ 123456studenti.unitn.it (L.T.); piergiuseppe.derosa2@ 123456unibo.it (P.D.R.); giovanni.perini@ 123456unibo.it (G.P.)
                Author notes
                Author information
                https://orcid.org/0000-0003-3228-0580
                https://orcid.org/0000-0002-7325-9908
                Article
                Publisher ID: genes-11-00556
                DOI: 10.3390/genes11050556
                PMC ID: 7288346
                PubMed ID: 32429325
                SO-VID: bdad64ee-78cd-43ab-8538-cca0d26cfa49
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 30 April 2020
                Date accepted : 11 May 2020
                Categories
                Subject: Review

                Keywords: histone deacetylases,hdac,chromatin,epigenetics,epigenomics,hdac inhibitors,hdaci,gene networks,cancer,phylogenesis
                Data availability:
                Keywords: histone deacetylases, hdac, chromatin, epigenetics, epigenomics, hdac inhibitors, hdaci, gene networks, cancer, phylogenesis

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