Science.gov

Sample records for histone deacetylases potential

  1. Histone Deacetylases

    PubMed Central

    Parbin, Sabnam; Kar, Swayamsiddha; Shilpi, Arunima; Sengupta, Dipta; Deb, Moonmoon; Rath, Sandip Kumar

    2014-01-01

    In the current era of genomic medicine, diseases are identified as manifestations of anomalous patterns of gene expression. Cancer is the principal example among such maladies. Although remarkable progress has been achieved in the understanding of the molecular mechanisms involved in the genesis and progression of cancer, its epigenetic regulation, particularly histone deacetylation, demands further studies. Histone deacetylases (HDACs) are one of the key players in the gene expression regulation network in cancer because of their repressive role on tumor suppressor genes. Higher expression and function of deacetylases disrupt the finely tuned acetylation homeostasis in both histone and non-histone target proteins. This brings about alterations in the genes implicated in the regulation of cell proliferation, differentiation, apoptosis and other cellular processes. Moreover, the reversible nature of epigenetic modulation by HDACs makes them attractive targets for cancer remedy. This review summarizes the current knowledge of HDACs in tumorigenesis and tumor progression as well as their contribution to the hallmarks of cancer. The present report also describes briefly various assays to detect histone deacetylase activity and discusses the potential role of histone deacetylase inhibitors as emerging epigenetic drugs to cure cancer. PMID:24051359

  2. Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?

    PubMed

    Harrison, Ian F; Dexter, David T

    2013-10-01

    Parkinson's disease (PD) is the most common movement disorder affecting more than 4million people worldwide. The primary motor symptoms of the disease are due to degeneration of dopaminergic nigrostriatal neurons. Dopamine replacement therapies have therefore revolutionised disease management by partially controlling these symptoms. However these drugs can produce debilitating side effects when used long term and do not protect degenerating neurons against death. Recent evidence has highlighted a pathological imbalance in PD between the acetylation and deacetylation of the histone proteins around which deoxyribonucleic acid (DNA) is coiled, in favour of excessive histone deacetylation. This mechanism of adding/removing acetyl groups to histone lysine residues is one of many epigenetic regulatory processes which control the expression of genes, many of which will be essential for neuronal survival. Hence, such epigenetic modifications may have a pathogenic role in PD. It has therefore been hypothesised that if this pathological imbalance can be corrected with the use of histone deacetylase inhibiting agents then neurodegeneration observed in PD can be ameliorated. This article will review the current literature with regard to epigenetic changes in PD and the use of histone deacetylase inhibitors (HDACIs) in PD: examining the evidence of the neuroprotective effects of numerous HDACIs in cellular and animal models of Parkinsonian cell death. Ultimately answering the question: does epigenetic targeting of histone deacetylases hold therapeutic potential in PD? PMID:23711791

  3. Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy

    PubMed Central

    Mohseni, Jafar; Zabidi-Hussin, Z.A.M.H.; Sasongko, Teguh Haryo

    2013-01-01

    Histone acetylation plays an important role in regulation of transcription in eukaryotic cells by promoting a more relaxed chromatin structure necessary for transcriptional activation. Histone deacetylases (HDACs) remove acetyl groups and suppress gene expression. HDAC inhibitors (HDACIs) are a group of small molecules that promote gene transcription by chromatin remodeling and have been extensively studied as potential drugs for treating of spinal muscular atrophy. Various drugs in this class have been studied with regard to their efficacy in increasing the expression of survival of motor neuron (SMN) protein. In this review, we discuss the current literature on this topic and summarize the findings of the main studies in this field. PMID:24130434

  4. Histone Deacetylases as Potential Targets for Cocaine Addiction.

    PubMed

    Kennedy, Pamela J; Harvey, Eric

    2015-01-01

    Drug-induced changes in gene expression likely contribute to long-lasting structural and functional alterations in the brain's reward circuitry and the persistence of addiction. Modulation of chromatin structure through covalent histone modifications has emerged as an important regulator of gene transcription in brain and increasing evidence suggests that misregulation of histone acetylation contributes to the establishment and maintenance of aberrant neuronal gene programs and behaviors associated with cocaine or amphetamine exposure. In this review, we summarize evidence supporting a role for histone acetylation in psychostimulant-induced plasticity and discuss findings from preclinical studies investigating histone deacetylase (HDAC) action and the use of small-molecule HDAC inhibitors (HDACis) to correct drug-mediated transcriptional dysregulation. PMID:26022264

  5. The Therapeutic Potential of Class I Selective Histone Deacetylase Inhibitors in Ovarian Cancer

    PubMed Central

    Khabele, Dineo

    2014-01-01

    Epithelial ovarian cancer remains the deadliest gynecologic malignancy. Despite advances in treatment, new approaches are needed. Histone deacetylases (HDACs) are a family of enzymes that regulate gene expression by removing acetyl groups from lysine residues on histones and non-histone proteins. Inhibition of HDACs with small molecules has led to the development of histone deacetylase inhibitors (HDACi) that are in clinical use, primarily for hematologic malignancies. Although clinical trials with HDACi as single agents in solid tumors have been disappointing, data from independent labs and recent work by our group show that class I selective HDACi have potent anti-tumor effects in pre-clinical models of ovarian cancer. This review summarizes the role of HDACs in ovarian cancer and the potential niche for selective class I HDACi, particularly HDAC3 in ovarian cancer therapy. PMID:24904826

  6. Histone deacetylases and atherosclerosis.

    PubMed

    Zheng, Xia-xia; Zhou, Tian; Wang, Xin-An; Tong, Xiao-hong; Ding, Jia-wang

    2015-06-01

    Atherosclerosis is the most common pathological process that leads to cardiovascular diseases, a disease of large- and medium-sized arteries that is characterized by a formation of atherosclerotic plaques consisting of necrotic cores, calcified regions, accumulated modified lipids, smooth muscle cells (SMCs), endothelial cells, leukocytes, and foam cells. Recently, the question about how to suppress the occurrence of atherosclerosis and alleviate the progress of cardiovascular disease becomes the hot topic. Accumulating evidence suggests that histone deacetylases(HDACs) play crucial roles in arteriosclerosis. This review summarizes the effect of HDACs and HDAC inhibitors(HDACi) on the progress of atherosclerosis. PMID:25875381

  7. Microinjection of histone deacetylase inhibitor into the ventrolateral orbital cortex potentiates morphine induced behavioral sensitization.

    PubMed

    Wei, Lai; Zhu, Yuan-Mei; Zhang, Yu-Xiang; Liang, Feng; Barry, Devin M; Gao, Hong-Yu; Li, Tao; Huo, Fu-Quan; Yan, Chun-Xia

    2016-09-01

    Accumulating evidence indicates that epigenetic regulation, such as changes in histone modification in reward-related brain regions, contributes to the memory formation of addiction to opiates and psychostimulants. Our recent results suggested that the ventrolateral orbital cortex (VLO) is involved in the memories of stress and drug addiction. Since addiction and stress memories share some common pathways, the present study was designed to investigate the role of histone deacetylase (HDAC) activity in the VLO during morphine induced-behavioral sensitization. Rats received a single exposure to morphine for establishing the behavioral sensitization model. The effect of HDAC activity in the VLO in morphine induced-behavioral sensitization was examined by microinjection of HDAC inhibitor Trichostatin A (TSA). Furthermore, the protein expression levels of extracellular signal-regulated kinase (ERK) and phosphorylated ERK (p-ERK), histone H3 lysine 9 acetylation (aceH3K9) and brain-derived neurotrophic factor (BDNF) in the VLO in morphine-induced behavioral sensitization were examined. The results showed that the bilateral VLO lesions suppressed the expression phase, but not the developmental phase of morphine-induced behavioral sensitization. Microinjection of TSA into the VLO significantly increased both the development and expression phases. Moreover, the protein levels of p-ERK, aceH3K9 and BDNF except ERK in the VLO were significantly upregulated in morphine-treated rats in the expression phase. These effects were further strengthened by intra-VLO injection of TSA. Our findings suggest that HDAC activity in the VLO could potentiate morphine-induced behavioral sensitization. The upregulated expression of p-ERK, aceH3K9 and BDNF in the VLO might be the underlying mechanism of histone acetylation enhancing the morphine-induced behavioral sensitization. PMID:27312092

  8. Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma.

    PubMed

    Stiff, Andrew; Caserta, Enrico; Sborov, Douglas W; Nuovo, Gerard J; Mo, Xiaokui; Schlotter, Sarah Y; Canella, Alessandro; Smith, Emily; Badway, Joseph; Old, Matthew; Jaime-Ramirez, Alena Cristina; Yan, Pearlly; Benson, Don M; Byrd, John C; Baiocchi, Robert; Kaur, Balveen; Hofmeister, Craig C; Pichiorri, Flavia

    2016-05-01

    Multiple myeloma remains incurable and the majority of patients die within 5 years of diagnosis. Reolysin, the infusible form of human reovirus (RV), is a novel viral oncolytic therapy associated with antitumor activity likely resulting from direct oncolysis and a virus-mediated antitumor immune response. Results from our phase I clinical trial investigating single agent Reolysin in patients with relapsed multiple myeloma confirmed tolerability, but no objective responses were evident, likely because the virus selectively entered the multiple myeloma cells but did not actively replicate. To date, the precise mechanisms underlying the RV infectious life cycle and its ability to induce oncolysis in patients with multiple myeloma remain unknown. Here, we report that junctional adhesion molecule 1 (JAM-1), the cellular receptor for RV, is epigenetically regulated in multiple myeloma cells. Treatment of multiple myeloma cells with clinically relevant histone deacetylase inhibitors (HDACi) results in increased JAM-1 expression as well as increased histone acetylation and RNA polymerase II recruitment to its promoter. Furthermore, our data indicate that the combination of Reolysin with HDACi, potentiates RV killing activity of multiple myeloma cells in vitro and in vivo This study provides the molecular basis to use these agents as therapeutic tools to increase the efficacy of RV therapy in multiple myeloma. Mol Cancer Ther; 15(5); 830-41. ©2016 AACR. PMID:26809490

  9. Beyond Histone and Deacetylase: An Overview of Cytoplasmic Histone Deacetylases and Their Nonhistone Substrates

    PubMed Central

    Yao, Ya-Li; Yang, Wen-Ming

    2011-01-01

    Acetylation of lysines is a prominent form of modification in mammalian proteins. Deacetylation of proteins is catalyzed by histone deacetylases, traditionally named after their role in histone deacetylation, transcriptional modulation, and epigenetic regulation. Despite the link between histone deacetylases and chromatin structure, some of the histone deacetylases reside in various compartments in the cytoplasm. Here, we review how these cytoplasmic histone deacetylases are regulated, the identification of nonhistone substrates, and the functional implications of their nondeacetylase enzymatic activities. PMID:21234400

  10. Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors.

    PubMed

    Galán, María; Varona, Saray; Orriols, Mar; Rodríguez, José Antonio; Aguiló, Silvia; Dilmé, Jaume; Camacho, Mercedes; Martínez-González, José; Rodriguez, Cristina

    2016-05-01

    Clinical management of abdominal aortic aneurysm (AAA) is currently limited to elective surgical repair because an effective pharmacotherapy is still awaited. Inhibition of histone deacetylase (HDAC) activity could be a promising therapeutic option in cardiovascular diseases. We aimed to characterise HDAC expression in human AAA and to evaluate the therapeutic potential of class I and IIa HDAC inhibitors in the AAA model of angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE(-/-)) mice. Real-time PCR, western blot and immunohistochemistry evidenced an increased expression of HDACs 1, 2 (both class I), 4 and 7 (both class IIa) in abdominal aorta samples from patients undergoing AAA open repair (n=22) compared with those from donors (n=14). Aortic aneurysms from Ang-II-infused ApoE(-/-) mice exhibited a similar HDAC expression profile. In these animals, treatment with a class I HDAC inhibitor (MS-275) or a class IIa inhibitor (MC-1568) improved survival, reduced the incidence and severity of AAA and limited aneurysmal expansion evaluated by Doppler ultrasonography. These beneficial effects were more potent in MC-1568-treated mice. The disorganisation of elastin and collagen fibres and lymphocyte and macrophage infiltration were effectively reduced by both inhibitors. Additionally, HDAC inhibition attenuated the exacerbated expression of pro-inflammatory markers and the increase in metalloproteinase-2 and -9 activity induced by Ang II in this model. Therefore, our data evidence that HDAC expression is deregulated in human AAA and that class-selective HDAC inhibitors limit aneurysm expansion in an AAA mouse model. New-generation HDAC inhibitors represent a promising therapeutic approach to overcome human aneurysm progression. PMID:26989193

  11. Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors

    PubMed Central

    Galán, María; Varona, Saray; Orriols, Mar; Rodríguez, José Antonio; Aguiló, Silvia; Dilmé, Jaume; Camacho, Mercedes; Martínez-González, José; Rodriguez, Cristina

    2016-01-01

    ABSTRACT Clinical management of abdominal aortic aneurysm (AAA) is currently limited to elective surgical repair because an effective pharmacotherapy is still awaited. Inhibition of histone deacetylase (HDAC) activity could be a promising therapeutic option in cardiovascular diseases. We aimed to characterise HDAC expression in human AAA and to evaluate the therapeutic potential of class I and IIa HDAC inhibitors in the AAA model of angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE−/−) mice. Real-time PCR, western blot and immunohistochemistry evidenced an increased expression of HDACs 1, 2 (both class I), 4 and 7 (both class IIa) in abdominal aorta samples from patients undergoing AAA open repair (n=22) compared with those from donors (n=14). Aortic aneurysms from Ang-II-infused ApoE−/− mice exhibited a similar HDAC expression profile. In these animals, treatment with a class I HDAC inhibitor (MS-275) or a class IIa inhibitor (MC-1568) improved survival, reduced the incidence and severity of AAA and limited aneurysmal expansion evaluated by Doppler ultrasonography. These beneficial effects were more potent in MC-1568-treated mice. The disorganisation of elastin and collagen fibres and lymphocyte and macrophage infiltration were effectively reduced by both inhibitors. Additionally, HDAC inhibition attenuated the exacerbated expression of pro-inflammatory markers and the increase in metalloproteinase-2 and -9 activity induced by Ang II in this model. Therefore, our data evidence that HDAC expression is deregulated in human AAA and that class-selective HDAC inhibitors limit aneurysm expansion in an AAA mouse model. New-generation HDAC inhibitors represent a promising therapeutic approach to overcome human aneurysm progression. PMID:26989193

  12. The potential use of histone deacetylase inhibitors in the treatment of depression.

    PubMed

    Fuchikami, Manabu; Yamamoto, Shigeto; Morinobu, Shigeru; Okada, Satoshi; Yamawaki, Yosuke; Yamawaki, Shigeto

    2016-01-01

    Numerous preclinical studies demonstrate that changes in gene expression in the brain occur in animal models of depression using exposure to stress, such as social defeat and leaned helplessness, and that repeated administration of antidepressants ameliorates these stress-induced changes in gene expression. These findings suggest that alteration in gene transcription in the central nervous system in response to stress plays an important role in the pathophysiology of depression. Recent advances in epigenetics have led to the realization that chromatin remodeling mediated by histone deacetylase (HDAC) is closely involved in the regulation of gene transcription. In this context, we first review several preclinical studies demonstrating the antidepressant-like efficacy of HDAC inhibitors. We then suggest the efficacy of HDAC inhibitors in treatment-resistant depression based on the mechanism of action of HDAC. Finally, we discuss the possibility of using HDAC inhibitors in patients with treatment-resistant depression. PMID:25818247

  13. Histone and Non-Histone Targets of Dietary Deacetylase Inhibitors.

    PubMed

    Kim, Eunah; Bisson, William H; Löhr, Christiane V; Williams, David E; Ho, Emily; Dashwood, Roderick H; Rajendran, Praveen

    2016-01-01

    Acetylation is an important, reversible post-translational modification affecting histone and non-histone proteins with critical roles in gene transcription, DNA replication, DNA repair, and cell cycle progression. Key regulatory enzymes include histone deacetylase (HDACs) and histone acetyltransferases (HATs). Overexpressed HDACs have been identified in many human cancers, resulting in repressed chromatin states that interfere with vital tumor suppressor functions. Inhibition of HDAC activity has been pursued as a mechanism for re-activating repressed genes in cancers, with some HDAC inhibitors showing promise in the clinical setting. Dietary compounds and their metabolites also have been shown to modulate HDAC activity or expression. Out of this body of research, attention increasingly has shifted towards non-histone targets of HDACs and HATs, such as transcriptions factors, hormone receptors, DNA repair proteins, and cytoskeletal components. These aspects are covered in present review, along with the possible clinical significance. Where such data are available, examples are cited from the literature of studies with short chain fatty acids, polyphenols, isoflavones, indoles, organosulfur compounds, organoselenium compounds, sesquiterpene lactones, isoflavones, and various miscellaneous agents. By virtue of their effects on both histone and non-histone proteins, dietary chemopreventive agents modulate the cellular acetylome in ways that are only now becoming apparent. A better understanding of the molecular mechanisms will likely enhance the potential to more effectively combat diseases harboring altered epigenetic landscapes and dysregulated protein signaling. PMID:26303421

  14. The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

    NASA Astrophysics Data System (ADS)

    Bürli, Roland W.; Thomas, Elizabeth; Beaumont, Vahri

    Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided.

  15. Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach

    PubMed Central

    Elbadawi, Mohamed A. Abdallah; Awadalla, Mohamed Khalid Alhaj; Abdel Hamid, Muzamil Mahdi; Mohamed, Magdi Awadalla; Awad, Talal Ahmed

    2015-01-01

    A new Plasmodium falciparum histone deacetylase1 (PfHDAC1) homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1. PMID:25679451

  16. Histone Deacetylases in Cartilage Homeostasis and Osteoarthritis.

    PubMed

    Carpio, Lomeli R; Westendorf, Jennifer J

    2016-08-01

    The involvement of the epigenome in complex diseases is becoming increasingly clear and more feasible to study due to new genomic and computational technologies. Moreover, therapies altering the activities of proteins that modify and interpret the epigenome are available to treat cancers and neurological disorders. Many additional uses have been proposed for these drugs based on promising preclinical results, including in arthritis models. Understanding the effects of epigenomic drugs on the skeleton is of interest because of its importance in maintaining overall health and fitness. In this review, we summarize ongoing advancements in how one class of epigenetic modifiers, histone deacetylases (Hdacs), controls normal cartilage development and homeostasis, as well as recent work aimed at understanding the alterations in the expression and activities of these enzymes in osteoarthritis (OA). We also review recent studies utilizing Hdac inhibitors and discuss the potential therapeutic benefits and limitations of these drugs for preventing cartilage destruction in OA. PMID:27402109

  17. An Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell Protection.

    PubMed

    Wagner, Florence F; Lundh, Morten; Kaya, Taner; McCarren, Patrick; Zhang, Yan-Ling; Chattopadhyay, Shrikanta; Gale, Jennifer P; Galbo, Thomas; Fisher, Stewart L; Meier, Bennett C; Vetere, Amedeo; Richardson, Sarah; Morgan, Noel G; Christensen, Dan Ploug; Gilbert, Tamara J; Hooker, Jacob M; Leroy, Mélanie; Walpita, Deepika; Mandrup-Poulsen, Thomas; Wagner, Bridget K; Holson, Edward B

    2016-02-19

    Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it has been difficult to dissect the role of individual HDACs due to a lack of selective small-molecule inhibitors. Here, we report the synthesis of a series of highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes to the clinically experienced HDAC inhibitor CI-994. We used this toolkit of isochemogenic or chemically matched inhibitors to probe the role of class I HDACs in β-cell pathobiology and demonstrate for the first time that selective inhibition of an individual HDAC isoform retains beneficial biological activity and mitigates mechanism-based toxicities. The highly selective HDAC3 inhibitor BRD3308 suppressed pancreatic β-cell apoptosis induced by inflammatory cytokines, as expected, or now glucolipotoxic stress, and increased functional insulin release. In addition, BRD3308 had no effect on human megakaryocyte differentiation, while inhibitors of HDAC1 and 2 were toxic. Our findings demonstrate that the selective inhibition of HDAC3 represents a potential path forward as a therapy to protect pancreatic β-cells from inflammatory cytokines and nutrient overload in diabetes. PMID:26640968

  18. Discovery of 1-hydroxypyridine-2-thiones as selective histone deacetylase inhibitors and their potential application for treating leukemia.

    PubMed

    Muthyala, Ramaiah; Shin, Woo Shik; Xie, Jiashu; Sham, Yuk Yin

    2015-10-01

    Histone deacetylase (HDAC) is a validated target for pursuing anticancer agents. However, obtaining a selective inhibitor against a given HDAC member remains a significant challenge. We report here the use of 1-hydroxypyridine-2-thione (1HPT) as a key pharmacophore for zinc-binding can result in highly selective HDAC inhibitors. 1HPT-6-carboxylic acid exhibits selective inhibition of HDAC6 with an IC50 of 150 nM that corresponds to a remarkable 0.9 ligand efficiency. Two analogs with simple amino acids shows nearly 600-fold selectivity among the eleven zinc-dependent HDACs. At low micromolar concentration these compounds inhibit the growth of HDAC8-overexpressing chronic myelogenous leukemia cells and specific form of acute myelogenous leukemia cells. Their potential mode of binding was examined by molecular docking and their stability was assessed in mouse and human plasma. Together the results suggest 1HPT analogs exhibit promising therapeutic potential for further development as anticancer agents to treat leukemia. PMID:26264503

  19. In silico modification of suberoylanilide hydroxamic acid (SAHA) as potential inhibitor for class II histone deacetylase (HDAC)

    PubMed Central

    2011-01-01

    Background The cervical cancer is the second most prevalent cancer for the woman in the world. It is caused by the oncogenic human papilloma virus (HPV). The inhibition activity of histone deacetylase (HDAC) is a potential strategy for cancer therapy. Suberoylanilide hydroxamic acid (SAHA) is widely known as a low toxicity HDAC inhibitor. This research presents in silico SAHA modification by utilizing triazole, in order to obtain a better inhibitor. We conducted docking of the SAHA inhibitor and 12 modified versions to six class II HDAC enzymes, and then proceeded with drug scanning of each one of them. Results The docking results show that the 12 modified inhibitors have much better binding affinity and inhibition potential than SAHA. Based on drug scan analysis, six of the modified inhibitors have robust pharmacological attributes, as revealed by drug likeness, drug score, oral bioavailability, and toxicity levels. Conclusions The binding affinity, free energy and drug scan screening of the best inhibitors have shown that 1c and 2c modified inhibitors are the best ones to inhibit class II HDAC. PMID:22373132

  20. Pharmacological doses of gamma-hydroxybutyrate (GHB) potentiate histone acetylation in the rat brain by histone deacetylase inhibition.

    PubMed

    Klein, Christian; Kemmel, Véronique; Taleb, Omar; Aunis, Dominique; Maitre, Michel

    2009-08-01

    Several small chain fatty acids, including butyrate, valproate, phenylbutyrate and its derivatives, inhibit several HDAC activities in the brain at a several hundred micromolar concentration. Gamma-hydroxy-butyrate (GHB), a natural compound found in the brain originating from the metabolism of GABA, is structurally related to these fatty acids. The average physiological tissue concentration of GHB in the brain is below 50 microM, but when GHB is administered or absorbed for therapeutic or recreative purposes, its concentration reaches several hundred micromolars. In the present scenario, we demonstrate that pharmacological concentrations of GHB significantly induce brain histone H3 acetylation with a heterogeneous distribution in the brain and reduce in vitro HDAC activity. The degree of HDAC inhibition was also different according to the region of the brain considered. Taking into account the multiple physiological and functional roles attributed to the modification of histone acetylation and its consequences at the level of gene expression, we propose that part of the therapeutic or toxic effects of high concentrations of GHB in the brain after therapeutic administration of the drug could be partly due to GHB-induced epigenetic factors. In addition, we hypothesize that GHB, being naturally synthesized in the cytosolic compartment of certain neurons, could penetrate into the nuclei and may reach sufficient levels that could significantly modulate histone acetylation and may participate in the epigenetic modification of gene expression. PMID:19427877

  1. Histone deacetylases: Targets for antifungal drug development

    PubMed Central

    Kmetzsch, Livia

    2015-01-01

    The interaction of pathogens and its hosts causes a drastic change in the transcriptional landscape in both cells. Among the several mechanisms of gene regulation, transcriptional initiation is probably the main point. In such scenario, the access of transcriptional machinery to promoter is highly regulated by post-translational modification of histones, such as acetylation, phosphorylation and others. Inhibition of histone deacetylases is able to reduce fungal pathogens fitness during infection and, therefore, is currently being considered for the development of new antifungal therapy strategies. PMID:26151486

  2. Functional characterization of Candida albicans Hos2 histone deacetylase

    PubMed Central

    Karthikeyan, G; Paul-Satyaseela, Maneesh; Dhatchana Moorthy, Nachiappan; Gopalaswamy, Radha; Narayanan, Shridhar

    2014-01-01

    Candida albicans is a mucosal commensal organism capable of causing superficial (oral and vaginal thrush) infections in immune normal hosts, but is a major pathogen causing systemic and mucosal infections in immunocompromised individuals. Azoles have been very effective anti-fungal agents and the mainstay in treating opportunistic mold and yeast infections. Azole resistant strains have emerged compromising the utility of this class of drugs. It has been shown that azole resistance can be reversed by the co-administration of a histone deacetylase (HDAC) inhibitor, suggesting that resistance is mediated by epigenetic mechanisms possibly involving Hos2, a fungal deacetylase. We report here the cloning and functional characterization of  HOS2 (High Osmolarity  Sensitive) , a gene coding for fungal histone deacetylase from  C. albicans. Inhibition studies showed that Hos2 is susceptible to pan inhibitors such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), but is not inhibited by class I inhibitors such as MS-275. This  in  vitro enzymatic assay, which is amenable to high throughput could be used for screening potent fungal Hos2 inhibitors that could be a potential anti-fungal adjuvant. Purified Hos2 protein consistently deacetylated tubulins, rather than histones from TSA-treated cells. Hos2 has been reported to be a putative NAD+ dependent histone deacetylase, a feature of sirtuins. We assayed for sirtuin activation with resveratrol and purified Hos2 protein and did not find any sirtuin activity. PMID:25110576

  3. Histone Deacetylases and Mechanisms of Regulation of Gene Expression (Histone deacetylases in cancer)

    PubMed Central

    Chen, Hong Ping; Zhao, Yu Tina; Zhao, Ting C

    2016-01-01

    In recent years, it has become widely recognized that histone modification plays a pivotal role in controlling gene expression, and is involved in a wide spectrum of disease regulation. Histone acetylation is a major modification that affects gene transcription and is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDAC). HATs acetylate lysines of histone proteins, resulting in relaxation of chromatin structure, and they also facilitate gene activation. Conversely, HDACs remove acetyl groups from hyperacetylated histones and suppress general gene transcription. In addition to histones, numerous non-histone proteins can be acetylated and deacetylated, and they are also involved in a wide range of disease regulation. To date, there are 18 HDACs in mammals classified into four classes based on homology to yeast HDACs. Accumulating evidence has revealed that HDACs play crucial roles in a variety of biological processes including inflammation, cell proliferation, apoptosis, and carcinogenesis. In this review, we summarize the current state of knowledge of HDACs in carcinogenesis and describe the involvement of HDACs in cancer-associated molecular processes. It is hoped than our understanding of the role of HDACs in cancer will lead to the design of more potent and specific drugs targeting selective HDAC proteins for the treatment of the disease. PMID:25746103

  4. FERRITIN H INDUCTION BY HISTONE DEACETYLASE INHIBITORS

    PubMed Central

    Wang, Wei; Di, Xiumin; Torti, Suzy V.; Torti, Frank M.

    2010-01-01

    Because both iron deficiency and iron excess are deleterious to normal cell function, the intracellular level of iron must be tightly controlled. Ferritin, an iron binding protein, regulates iron balance by storing iron in a bioavailable but non-toxic form. Ferritin protein comprises two subunits: ferritin H, which contains ferroxidase activity, and ferritin L. Here we demonstrate that ferritin H mRNA and protein are induced by histone deacetylase inhibitors (HDAC inhibitors), a promising class of anti-cancer drugs, in cultured human cancer cells. Deletion analysis and EMSA assays reveal that the induction of ferritin H occurs at a transcriptional level via Sp1 and NF-Y binding sites near the transcriptional start site of the human ferritin H promoter. Classically, HDAC inhibitors modulate gene expression by increasing histone acetylation. However, ChIP assays demonstrate that HDAC inhibitors induce ferritin H transcription by increasing NF-Y binding to the ferritin H promoter without changes in histone acetylation. These results identify ferritin H as a new target of HDAC inhibitors, and recruitment of NF-Y as a novel mechanism of action of HDAC inhibitors. PMID:20385107

  5. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma

    PubMed Central

    Mazur, Pawel K; Herner, Alexander; Mello, Stephano S; Wirth, Matthias; Hausmann, Simone; Sánchez-Rivera, Francisco J; Lofgren, Shane M; Kuschma, Timo; Hahn, Stephan A; Vangala, Deepak; Trajkovic-Arsic, Marija; Gupta, Aayush; Heid, Irina; Noël, Peter B; Braren, Rickmer; Erkan, Mert; Kleeff, Jörg; Sipos, Bence; Sayles, Leanne C; Heikenwalder, Mathias; Heßmann, Elisabeth; Ellenrieder, Volker; Esposito, Irene; Jacks, Tyler; Bradner, James E; Khatri, Purvesh; Sweet-Cordero, E Alejandro; Attardi, Laura D; Schmid, Roland M; Schneider, Guenter; Sage, Julien; Siveke, Jens T

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9–based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy–induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors. PMID:26390243

  6. Histone deacetylase inhibitors as cancer therapeutics

    PubMed Central

    2016-01-01

    Cancer cells contain significant alterations in their epigenomic landscape, which several enzyme families reversibly contribute to. One class of epigenetic modifying enzymes is that of histone deacetylases (HDAC), which are receiving considerable scrutiny clinically as a therapeutic target in many cancers. The underlying rationale is that inhibiting HDACs will reverse dysregulated target gene expression by modulating functional histone (or other) acetylation marks. This perspective will discuss a recent paper by Markozashvili and co-workers which appeared in Gene, which indicates that the mechanisms by which HDAC inhibitors (HDACis) alter the epigenetic landscape include widespread alternative effects beyond simply controlling regional epigenetic marks. HDACs are involved in many processes/diseases, and it is not surprising that HDACis have considerable off-target effects, and thus a major effort is being directed toward identification of inhibitors which are selective for HDAC isoforms often uniquely implicated in various cancers. This Perspective will also discuss some representative work with inhibitors targeting individual HDAC classes or isoforms. At present, it is not really clear that isoform-specific HDACis will avoid non-selective effects on other unrecognized activities of HDACs. PMID:27568481

  7. Histone deacetylase inhibitors as cancer therapeutics.

    PubMed

    Clawson, Gary A

    2016-08-01

    Cancer cells contain significant alterations in their epigenomic landscape, which several enzyme families reversibly contribute to. One class of epigenetic modifying enzymes is that of histone deacetylases (HDAC), which are receiving considerable scrutiny clinically as a therapeutic target in many cancers. The underlying rationale is that inhibiting HDACs will reverse dysregulated target gene expression by modulating functional histone (or other) acetylation marks. This perspective will discuss a recent paper by Markozashvili and co-workers which appeared in Gene, which indicates that the mechanisms by which HDAC inhibitors (HDACis) alter the epigenetic landscape include widespread alternative effects beyond simply controlling regional epigenetic marks. HDACs are involved in many processes/diseases, and it is not surprising that HDACis have considerable off-target effects, and thus a major effort is being directed toward identification of inhibitors which are selective for HDAC isoforms often uniquely implicated in various cancers. This Perspective will also discuss some representative work with inhibitors targeting individual HDAC classes or isoforms. At present, it is not really clear that isoform-specific HDACis will avoid non-selective effects on other unrecognized activities of HDACs. PMID:27568481

  8. Potential Prognostic Value of Histone Deacetylase 6 and Acetylated Heat-Shock Protein 90 in Early-Stage Breast Cancer

    PubMed Central

    Park, Younghee; Lee, Kyu Sang; Park, So Yeon; Kim, Jee Hyun; Kang, Eun Young; Kim, Sung Won; Eom, Keon Young; Kim, Jae Sung

    2015-01-01

    Purpose Histone deacetylase 6 (HDAC6) is an enzyme that deacetylates heat-shock protein 90 (HSP90). Many studies have investigated the role of HDAC6 and HSP90 in tumorigenesis and in the prognosis of cancer patients. This study aimed to evaluate the prognostic value of HDAC6 and acetylated HSP90 (acetyl-HSP90) in a cohort of breast cancer patients. Methods Immunohistochemical analysis of 314 surgical specimens obtained from patients with invasive breast cancer was carried out to assess standard pathologic factors and the expression of HDAC6 and acetyl-HSP90. Statistical analyses were performed to determine the association between HDAC6, acetyl-HSP90, and conventional clinicopathological factors, and the prognostic values of these factors were evaluated. Results HDAC6 expression did not show any correlation with other clinicopathological factors, but acetyl-HSP90 was significantly correlated with histologic grade (p=0.001) and the Ki-67 index (p=0.015). HDAC6 and acetyl-HSP90 expression were significantly associated with each other (p=0.047). Although HDAC6 was not prognostic for disease-free survival (DFS), some patients with high expression of HDAC6 experienced recurrence 5 years after diagnosis, while there was no recurrent disease after 5 years in those with low expression. Acetyl-HSP90 was significantly associated with the DFS of all patients (p=0.016) and with high HDAC6 expression (p=0.017), but not with low expression. Conclusion Expression of HDAC6 and acetyl-HSP90 are correlated. HDAC6 is proposed to be a possible predictive marker of late recurrence, and acetyl-HSP90 has prognostic value in predicting the DFS of breast cancer patients. PMID:26472975

  9. Targeting histone deacetylases: A novel therapeutic strategy for atrial fibrillation.

    PubMed

    Lkhagva, Baigalmaa; Kao, Yu-Hsun; Chen, Yao-Chang; Chao, Tze-Fan; Chen, Shih-Ann; Chen, Yi-Jen

    2016-06-15

    Atrial fibrillation (AF) is a common cardiac arrhythmia associated with high mortality and morbidity. Current treatments of AF have limited efficacy and considerable side effects. Histone deacetylases (HDACs) play critical roles in the pathophysiology of cardiovascular diseases and contribute to the genesis of AF. Therefore, HDAC inhibition may prove a novel therapeutic strategy for AF through upstream therapy and modifications of AF electrical and structural remodeling. In this review, we provide an update of the knowledge of the effects of HDACs and HDAC inhibitors on AF, and dissect potential underlying mechanisms. PMID:27089819

  10. Effect of histone deacetylase on prostate carcinoma

    PubMed Central

    Zhang, Yuanfeng; Xu, Qingchun; Liu, Guoyuan; Huang, Hong; Lin, Weiqiang; Huang, Yueying; Chi, Zepai; Chen, Shaochuan; Lan, Kaijian; Lin, Jiahua; Zhang, Yonghai

    2015-01-01

    Commonly occurred in aged males, the incidence of prostate carcinoma is increasing by years. Histone deacetylase (HDACs) as one key enzyme in regulating gene transcription has been found to be related with cancer occurrence. Trichostatin A (TSA) is one HDAC inhibitor for suppressing tumor growth. This study thus treated prostate carcinoma cell line PC3 with TSA, to analyze the effect of HDAC on the occurrence and progression of HDAC. PC3 cells were treated with gradient concentrations of TSA. MTT assay was employed to detect the proliferation of PC3 cells, while flow cytometry was used to detect the cell apoptosis and cell cycle. Apoptotic proteins including caspase-3, caspase-9 and bcl-2 were further quantified by Western blotting. MTT assays showed a dose- and time-dependent manner of TSA in inhibiting PC3 cell proliferation. Most of PC3 cells were arrested at G1 phase after treating with TSA. The apoptotic ratio of cells was also elevated by higher concentrations of drugs. Apoptotic proteins including caspase-3, caspase-9 and bcl-2 were all up-regulated by TSA. HDAC inhibitor can effectively suppress the proliferation of prostate carcinoma cells, which can be arrested at G1 phase. The elevated apoptotic ratio was caused by up-regulation of apoptosis-related proteins caspase-3, caspase-9 and bcl-2, in both dose- and time-dependent manners. PMID:26823840

  11. Interpreting clinical assays for histone deacetylase inhibitors

    PubMed Central

    Martinet, Nadine; Bertrand, Philippe

    2011-01-01

    As opposed to genetics, dealing with gene expressions by direct DNA sequence modifications, the term epigenetics applies to all the external influences that target the chromatin structure of cells with impact on gene expression unrelated to the sequence coding of DNA itself. In normal cells, epigenetics modulates gene expression through all development steps. When “imprinted” early by the environment, epigenetic changes influence the organism at an early stage and can be transmitted to the progeny. Together with DNA sequence alterations, DNA aberrant cytosine methylation and microRNA deregulation, epigenetic modifications participate in the malignant transformation of cells. Their reversible nature has led to the emergence of the promising field of epigenetic therapy. The efforts made to inhibit in particular the epigenetic enzyme family called histone deacetylases (HDACs) are described. HDAC inhibitors (HDACi) have been proposed as a viable clinical therapeutic approach for the treatment of leukemia and solid tumors, but also to a lesser degree for noncancerous diseases. Three epigenetic drugs are already arriving at the patient’s bedside, and more than 100 clinical assays for HDACi are registered on the National Cancer Institute website. They explore the eventual additive benefits of combined therapies. In the context of the pleiotropic effects of HDAC isoforms, more specific HDACi and more informative screening tests are being developed for the benefit of the patients. PMID:21625397

  12. Dual Inhibitors Against Topoisomerases and Histone Deacetylases

    PubMed Central

    Seo, Young Ho

    2015-01-01

    Topoisomerases and histone deacetylases (HDACs) are considered as important therapeutic targets for a wide range of cancers, due to their association with the initiation, proliferation and survival of cancer cells. Topoisomerases are involved in the cleavage and religation processes of DNA, while HDACs regulate a dynamic epigenetic modification of the lysine amino acid on various proteins. Extensive studies have been undertaken to discover small molecule inhibitor of each protein and thereby, several drugs have been transpired from this effort and successfully approved for clinical use. However, the inherent heterogeneity and multiple genetic abnormalities of cancers challenge the clinical application of these single targeted drugs. In order to overcome the limitations of a single target approach, a novel approach, simultaneously targeting topoisomerases and HDACs with a single molecule has been recently employed and attracted much attention of medicinal chemists in drug discovery. This review highlights the current studies on the discovery of dual inhibitors against topoisomerases and HDACs, provides their pharmacological aspects and advantages, and discusses the challenges and promise of the dual inhibitors. PMID:26151040

  13. Suppression of caspase-11 expression by histone deacetylase inhibitors

    SciTech Connect

    Heo, Hyejung; Yoo, Lang; Shin, Ki Soon; Kang, Shin Jung

    2009-01-02

    It has been well documented that histone deacetylase inhibitors suppress inflammatory gene expression. Therefore, we investigated whether histone deacetylase inhibitors modulate the expression of caspase-11 that is known as an inducible caspase regulating both inflammation and apoptosis. In the present study, we show that sodium butyrate and trichostatin A, two structurally unrelated inhibitors of histone deacetylase (HDAC), effectively suppressed the induction of caspase-11 in mouse embryonic fibroblasts stimulated with lipopolysaccharides. Sodium butyrate inhibited the activation of upstream signaling events for the caspase-11 induction such as activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, degradation of inhibitor of {kappa}B, and activation of nuclear factor-{kappa}B. These results suggest that the HDAC inhibitor suppressed cytosolic signaling events for the induction of caspase-11 by inhibiting the deacetylation of non-histone proteins.

  14. Targeting Histone Deacetylases: A Novel Approach in Parkinson's Disease

    PubMed Central

    Sharma, Sorabh; Taliyan, Rajeev

    2015-01-01

    The worldwide prevalence of movement disorders is increasing day by day. Parkinson's disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in both in vivo and in vitro models of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD. PMID:25694842

  15. Inhibitors of histone deacetylase as antitumor agents: A critical review.

    PubMed

    Manal, Mohammed; Chandrasekar, M J N; Gomathi Priya, Jeyapal; Nanjan, M J

    2016-08-01

    Histone deacetylase (EC 3.5.1.98 - HDAC) is an amidohydrolase involved in deacetylating the histone lysine residues for chromatin remodeling and thus plays a vital role in the epigenetic regulation of gene expression. Due to its aberrant activity and over expression in several forms of cancer, HDAC is considered as a potential anticancer drug target. HDAC inhibitors alter the acetylation status of histone and non-histone proteins to regulate various cellular events such as cell survival, differentiation and apoptosis in tumor cells and thus exhibit anticancer activity. Till date, four drugs, namely Vorinostat (SAHA), Romidepsin (FK-228), Belinostat (PXD-101) and Panobinostat (LBH-589) have been granted FDA approval for cancer and several HDAC inhibitors are currently in various phases of clinical trials, either as monotherapy and/or in combination with existing/novel anticancer agents. Regardless of this, today scientific efforts have fortified the quest for newer and novel HDAC inhibitors that show isoform selectivity. This review focuses on the chemistry of the molecules of two classes of HDAC inhibitors, namely short chain fatty acids and hydroxamic acids, investigated so far as novel therapeutic agents for cancer. PMID:27239721

  16. Histone Deacetylase 9 Is a Negative Regulator of Adipogenic Differentiation*

    PubMed Central

    Chatterjee, Tapan K.; Idelman, Gila; Blanco, Victor; Blomkalns, Andra L.; Piegore, Mark G.; Weintraub, Daniel S.; Kumar, Santosh; Rajsheker, Srinivas; Manka, David; Rudich, Steven M.; Tang, Yaoliang; Hui, David Y.; Bassel-Duby, Rhonda; Olson, Eric N.; Lingrel, Jerry B.; Ho, Shuk-Mei; Weintraub, Neal L.

    2011-01-01

    Differentiation of preadipocytes into mature adipocytes capable of efficiently storing lipids is an important regulatory mechanism in obesity. Here, we examined the involvement of histone deacetylases (HDACs) and histone acetyltransferases (HATs) in the regulation of adipogenesis. We find that among the various members of the HDAC and HAT families, only HDAC9 exhibited dramatic down-regulation preceding adipogenic differentiation. Preadipocytes from HDAC9 gene knock-out mice exhibited accelerated adipogenic differentiation, whereas HDAC9 overexpression in 3T3-L1 preadipocytes suppressed adipogenic differentiation, demonstrating its direct role as a negative regulator of adipogenesis. HDAC9 expression was higher in visceral as compared with subcutaneous preadipocytes, negatively correlating with their potential to undergo adipogenic differentiation in vitro. HDAC9 localized in the nucleus, and its negative regulation of adipogenesis segregates with the N-terminal nuclear targeting domain, whereas the C-terminal deacetylase domain is dispensable for this function. HDAC9 co-precipitates with USF1 and is recruited with USF1 at the E-box region of the C/EBPα gene promoter in preadipocytes. Upon induction of adipogenic differentiation, HDAC9 is down-regulated, leading to its dissociation from the USF1 complex, whereas p300 HAT is up-regulated to allow its association with USF1 and accumulation at the E-box site of the C/EBPα promoter in differentiated adipocytes. This reciprocal regulation of HDAC9 and p300 HAT in the USF1 complex is associated with increased C/EBPα expression, a master regulator of adipogenic differentiation. These findings provide new insights into mechanisms of adipogenic differentiation and document a critical regulatory role for HDAC9 in adipogenic differentiation through a deacetylase-independent mechanism. PMID:21680747

  17. Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia

    PubMed Central

    Ceccacci, Elena; Minucci, Saverio

    2016-01-01

    Histone deacetylases (HDACs) are a key component of the epigenetic machinery regulating gene expression, and behave as oncogenes in several cancer types, spurring the development of HDAC inhibitors (HDACi) as anticancer drugs. This review discusses new results regarding the role of HDACs in cancer and the effect of HDACi on tumour cells, focusing on haematological malignancies, particularly acute myeloid leukaemia. Histone deacetylases may have opposite roles at different stages of tumour progression and in different tumour cell sub-populations (cancer stem cells), highlighting the importance of investigating these aspects for further improving the clinical use of HDACi in treating cancer. PMID:26908329

  18. Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia.

    PubMed

    Ceccacci, Elena; Minucci, Saverio

    2016-03-15

    Histone deacetylases (HDACs) are a key component of the epigenetic machinery regulating gene expression, and behave as oncogenes in several cancer types, spurring the development of HDAC inhibitors (HDACi) as anticancer drugs. This review discusses new results regarding the role of HDACs in cancer and the effect of HDACi on tumour cells, focusing on haematological malignancies, particularly acute myeloid leukaemia. Histone deacetylases may have opposite roles at different stages of tumour progression and in different tumour cell sub-populations (cancer stem cells), highlighting the importance of investigating these aspects for further improving the clinical use of HDACi in treating cancer. PMID:26908329

  19. The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases

    PubMed Central

    van den Bosch, Thea; Boichenko, Alexander; Leus, Niek G. J.; Eleni Ourailidou, Maria; Wapenaar, Hannah; Rotili, Dante; Mai, Antonello; Imhof, Axel; Bischoff, Rainer; Haisma, Hidde J.; Dekker, Frank J.

    2016-01-01

    Lysine acetylations are reversible posttranslational modifications of histone and non-histone proteins that play important regulatory roles in signal transduction cascades and gene expression. Lysine acetylations are regulated by histone acetyltransferases as writers and histone deacetylases as erasers. Because of their role in signal transduction cascades, these enzymes are important players in inflammation. Therefore, applications of histone acetyltransferase inhibitors to reduce inflammatory responses are interesting. Among the few histone acetyltransferase inhibitors described, C646 is one of the most potent (Ki of 0.4 μM for histone acetyltransferase p300). C646 was described to regulate the NF-κB pathway; an important pathway in inflammatory responses, which is regulated by acetylation. Interestingly, this pathway has been implicated in asthma and COPD. Therefore we hypothesized that via regulation of the NF-κB signaling pathway, C646 can inhibit pro-inflammatory gene expression, and have potential for the treatment of inflammatory lung diseases. In line with this, here we demonstrate that C646 reduces pro-inflammatory gene expression in RAW264.7 murine macrophages and murine precision-cut lung slices. To unravel its effects on cellular substrates we applied mass spectrometry and found, counterintuitively, a slight increase in acetylation of histone H3. Based on this finding, and structural features of C646, we presumed inhibitory activity of C646 on histone deacetylases, and indeed found inhibition of histone deacetylases from 7 μM and higher concentrations. This indicates that C646 has potential for further development towards applications in the treatment of inflammation, however, its newly discovered lack of selectivity at higher concentrations needs to be taken into account. PMID:26718586

  20. The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases.

    PubMed

    van den Bosch, Thea; Boichenko, Alexander; Leus, Niek G J; Ourailidou, Maria E; Wapenaar, Hannah; Rotili, Dante; Mai, Antonello; Imhof, Axel; Bischoff, Rainer; Haisma, Hidde J; Dekker, Frank J

    2016-02-15

    Lysine acetylations are reversible posttranslational modifications of histone and non-histone proteins that play important regulatory roles in signal transduction cascades and gene expression. Lysine acetylations are regulated by histone acetyltransferases as writers and histone deacetylases as erasers. Because of their role in signal transduction cascades, these enzymes are important players in inflammation. Therefore, histone acetyltransferase inhibitors could reduce inflammatory responses. Among the few histone acetyltransferase inhibitors described, C646 is one of the most potent (Ki of 0.4μM for histone acetyltransferase p300). C646 was described to affect the NF-κB pathway; an important pathway in inflammatory responses, which is regulated by acetylation. This pathway has been implicated in asthma and COPD. Therefore, we hypothesized that via regulation of the NF-κB signaling pathway, C646 can inhibit pro-inflammatory gene expression, and have potential for the treatment of inflammatory lung diseases. In line with this, we demonstrate here that C646 reduces pro-inflammatory gene expression in RAW264.7 murine macrophages and murine precision-cut lung slices. To unravel its effects on cellular substrates we applied mass spectrometry and found, counterintuitively, a slight increase in acetylation of histone H3. Based on this finding, and structural features of C646, we presumed inhibitory activity of C646 on histone deacetylases, and indeed found inhibition of histone deacetylases from 7μM and higher concentrations. This indicates that C646 has potential for further development towards applications in the treatment of inflammation, however, its newly discovered lack of selectivity at higher concentrations needs to be taken into account. PMID:26718586

  1. Histone deacetylase 9 regulates breast cancer cell proliferation and the response to histone deacetylase inhibitors

    PubMed Central

    Lapierre, Marion; Linares, Aurélien; Dalvai, Mathieu; Duraffourd, Céline; Bonnet, Sandrine; Boulahtouf, Abdelhay; Rodriguez, Carmen; Jalaguier, Stéphan; Assou, Said; Orsetti, Beatrice; Balaguer, Patrick; Maudelonde, Thierry; Blache, Philippe; Bystricky, Kerstin; Boulle, Nathalie; Cavaillès, Vincent

    2016-01-01

    Histone lysine acetylation is an epigenetic mark regulated by histone acetyltransferases and histone deacetylases (HDAC) which plays an important role in tumorigenesis. In this study, we observed a strong overexpression of class IIa HDAC9, at the mRNA and protein levels, in the most aggressive human breast cancer cell lines (i.e. in basal breast cancer cells vs luminal ones or in malignant vs begnin MCF10A breast epithelial cell lines). HDAC9 overexpression was associated with higher rates of gene transcription and increased epigenetic marks on the HDAC9 promoter. Ectopic expression of HDAC9 in MCF7 luminal breast cancer cells led to an increase in cell proliferation and to a decrease in apoptosis. These effects were associated with a deregulated expression of several genes controlled by HDAC inhibitors such as CDKN1A, BAX and TNFRSF10A. Inversely, knock-down of HDAC9 expression in MDA-MB436 basal breast cancer cells reduced cell proliferation. Moreover, high HDAC9 expression decreased the efficacy of HDAC inhibitors to reduce cell proliferation and to regulate CDKN1A gene expression. Interestingly, the gene encoding the transcription factor SOX9 was identified by a global transcriptomic approach as an HDAC9 target gene. In stably transfected MCF7 cells, SOX9 silencing significantly decreased HDAC9 mitogenic activity. Finally, in a large panel of breast cancer biopsies, HDAC9 expression was significantly increased in tumors of the basal subtype, correlated with SOX9 expression and associated with poor prognosis. Altogether, these results indicate that HDAC9 is a key factor involved in mammary carcinogenesis and in the response to HDAC inhibitors. PMID:26930713

  2. Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights

    PubMed Central

    Bose, Prithviraj; Dai, Yun; Grant, Steven

    2014-01-01

    Initially regarded as “epigenetic modifiers” acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clinical studies. In recent years, additional mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clinical potential, the clinical use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discuss synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer. PMID:24769080

  3. The Histone Deacetylase Complex 1 Protein of Arabidopsis Has the Capacity to Interact with Multiple Proteins Including Histone 3-Binding Proteins and Histone 1 Variants1[OPEN

    PubMed Central

    Carr, Craig; Asensi-Fabado, Maria A.; Donald, Naomi A.; Hannah, Matthew A.; Amtmann, Anna

    2016-01-01

    Intrinsically disordered proteins can adopt multiple conformations, thereby enabling interaction with a wide variety of partners. They often serve as hubs in protein interaction networks. We have previously shown that the Histone Deacetylase Complex 1 (HDC1) protein from Arabidopsis (Arabidopsis thaliana) interacts with histone deacetylases and quantitatively determines histone acetylation levels, transcriptional activity, and several phenotypes, including abscisic acid sensitivity during germination, vegetative growth rate, and flowering time. HDC1-type proteins are ubiquitous in plants, but they contain no known structural or functional domains. Here, we explored the protein interaction spectrum of HDC1 using a quantitative bimolecular fluorescence complementation assay in tobacco (Nicotiana benthamiana) epidermal cells. In addition to binding histone deacetylases, HDC1 directly interacted with histone H3-binding proteins and corepressor-associated proteins but not with H3 or the corepressors themselves. Surprisingly, HDC1 also was able to interact with variants of the linker histone H1. Truncation of HDC1 to the ancestral core sequence narrowed the spectrum of interactions and of phenotypic outputs but maintained binding to a H3-binding protein and to H1. Thus, HDC1 provides a potential link between H1 and histone-modifying complexes. PMID:26951436

  4. A phosphorescent rhenium(I) histone deacetylase inhibitor: mitochondrial targeting and paraptosis induction.

    PubMed

    Ye, Rui-Rong; Tan, Cai-Ping; Lin, Yan-Nan; Ji, Liang-Nian; Mao, Zong-Wan

    2015-05-14

    In this report, we designed a histone deacetylase-targeted phosphorescent Re(I) complex ReLMito. Colocalization studies suggested that ReLMito could specially localize to mitochondria. We also demonstrated that ReLMito could induce paraptosis in cancer cells. These features endowed the complex with potential to induce and monitor mitochondrial morphological changes during the paraptosis simultaneously. PMID:25882790

  5. Structure of Prokaryotic Polyamine Deacetylase Reveals Evolutionary Functional Relationships with Eukaryotic Histone Deacetylases

    SciTech Connect

    P Lombardi; H Angell; D Whittington; E Flynn; K Rajashankar; D Christianson

    2011-12-31

    Polyamines are a ubiquitous class of polycationic small molecules that can influence gene expression by binding to nucleic acids. Reversible polyamine acetylation regulates nucleic acid binding and is required for normal cell cycle progression and proliferation. Here, we report the structures of Mycoplana ramosa acetylpolyamine amidohydrolase (APAH) complexed with a transition state analogue and a hydroxamate inhibitor and an inactive mutant complexed with two acetylpolyamine substrates. The structure of APAH is the first of a histone deacetylase-like oligomer and reveals that an 18-residue insert in the L2 loop promotes dimerization and the formation of an 18 {angstrom} long 'L'-shaped active site tunnel at the dimer interface, accessible only to narrow and flexible substrates. The importance of dimerization for polyamine deacetylase function leads to the suggestion that a comparable dimeric or double-domain histone deacetylase could catalyze polyamine deacetylation reactions in eukaryotes.

  6. Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

    PubMed Central

    Sumanadasa, Subathdrage D. M.; Goodman, Christopher D.; Lucke, Andrew J.; Skinner-Adams, Tina; Sahama, Ishani; Haque, Ashraful; Do, Tram Anh; McFadden, Geoffrey I.; Fairlie, David P.

    2012-01-01

    Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, the in vitro and in vivo antiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth of Plasmodium falciparum asexual-stage parasites in vitro (50% inhibitory concentration [IC50], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited the in vitro growth of exoerythrocytic-stage Plasmodium parasites in liver cells (IC50, ∼150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimental in vivo murine model of cerebral malaria, orally administered SB939 significantly inhibited P. berghei ANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria. PMID:22508312

  7. Inhibitors of Histone Deacetylases Attenuate Noise-Induced Hearing Loss.

    PubMed

    Chen, Jun; Hill, Kayla; Sha, Su-Hua

    2016-08-01

    Loss of auditory sensory hair cells is the major pathological feature of noise-induced hearing loss (NIHL). Currently, no established clinical therapies for prevention or amelioration of NIHL are available. The absence of treatments is due to our lack of a comprehensive understanding of the molecular mechanisms underlying noise-induced damage. Our previous study indicates that epigenetic modification of histones alters hair cell survival. In this study, we investigated the effect of noise exposure on histone H3 lysine 9 acetylation (H3K9ac) in the inner ear of adult CBA/J mice and determined if inhibition of histone deacetylases by systemic administration of suberoylanilide hydroxamic acid (SAHA) could attenuate NIHL. Our results showed that H3K9ac was decreased in the nuclei of outer hair cells (OHCs) and marginal cells of the stria vascularis in the basal region after exposure to a traumatic noise paradigm known to induce permanent threshold shifts (PTS). Consistent with these results, levels of histone deacetylases 1, 2, and 3 (HDAC1, HDAC2 and HDAC3) were increased predominately in the nuclei of cochlear cells. Silencing of HDAC1, HDAC2, or HDAC3 with siRNA reduced the expression of the target HDAC in OHCs, but did not attenuate noise-induced PTS, whereas treatment with the pan-HDAC inhibitor SAHA, also named vorinostat, reduced OHC loss, and attenuated PTS. These findings suggest that histone acetylation is involved in the pathogenesis of noise-induced OHC death and hearing loss. Pharmacological targeting of histone deacetylases may afford a strategy for protection against NIHL. PMID:27095478

  8. Targeting Histone Deacetylases in Diseases: Where Are We?

    PubMed Central

    Benedetti, Rosaria; Conte, Mariarosaria

    2015-01-01

    Abstract Significance: Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of histone deacetylases (HDACs) and histone acetyltransferases is one epigenetic mechanism controlling gene expression and is, thus, associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization, and death. Recent Advances: Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy. Critical Issues: (i) Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. (ii) Advantages/disadvantages of non-selective or isoform-directed HDACi. (iii) Limited number of response-predictive biomarkers. (iv) Toxicity leading to dysfunction of critical biological processes. Future Directions: Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers, enabling better patient stratification and prediction of response to treatment. Antioxid. Redox Signal. 23, 99–126. PMID:24382114

  9. Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for non-small-cell lung cancer cells.

    PubMed

    Takashina, Taichi; Kinoshita, Ichiro; Kikuchi, Junko; Shimizu, Yasushi; Sakakibara-Konishi, Jun; Oizumi, Satoshi; Nishimura, Masaharu; Dosaka-Akita, Hirotoshi

    2016-07-01

    Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), is frequently overexpressed in non-small-cell lung cancer (NSCLC) and that an EZH2 inhibitor, 3-deazaneplanocin A, inhibits the proliferation of NSCLC cells. Transcriptional silencing by EZH2 was recently shown to be required for the activity of histone deacetylases (HDACs) that interact with another PRC2 protein, EED. To develop a more effective epigenetic therapy for NSCLC, we determined the effects of co-treatment with 3-deazaneplanocin A and the HDAC inhibitor vorinostat (SAHA) in NSCLC cells. The co-treatment synergistically suppressed the proliferation of all tested NSCLC cell lines, regardless of their epidermal growth factor receptor (EGFR) status. The synergistic effect was associated with slightly decreased histone H3 lysine 27 trimethylation, modestly increased histone acetylation, and the depletion of EZH2 and other PRC2 proteins. The co-treatment resulted in an accumulation of p27Kip1, decrease in cyclin A, and increased apoptotic fraction in an additive/synergistic manner. Interestingly, the co-treatment strongly suppressed EGFR signaling, not only in EGFR-wild-type NSCLC cells, but also in EGFR-mutant cells, mainly through dephosphorylation of EGFR. Furthermore, the co-treatment suppressed the in vivo tumor growth of EGFR-mutant, EGFR-tyrosine kinase-resistant H1975 cells more effectively than did each agent alone, without visible toxicity. These results suggest that the combined pharmacological targeting of EZH2 and HDACs may provide more effective epigenetic therapeutics for NSCLC. PMID:27116120

  10. Selectively Targeting Prostate Cancer with Antiandrogen Equipped Histone Deacetylase Inhibitors

    PubMed Central

    Gryder, Berkley E.; Akbashev, Michelle J.; Rood, Michael K.; Raftery, Eric D.; Meyers, Warren M.; Dillard, Paulette; Khan, Shafiq; Oyelere, Adegboyega K.

    2013-01-01

    Diverse cellular processes relevant to cancer progression are regulated by the acetylation status of proteins. Among such processes is chromatin remodeling via histone proteins, controlled by opposing histone deacetylase (HDAC) and histone acetyltransferase (HAT) enzymes. Histone deacetylase inhibitors (HDACi) show great promise in preclinical cancer models, but clinical trials treating solid tumors have failed to improve patient survival. This is due in part to an inability of HDACi to effectively accumulate in cancerous cells. To address this problem we designed HDACi with secondary pharmacophores to facilitate selective accumulation in malignant cells. We present the first example of HDACi compounds targeted to prostate tumors by equipping them with the additional ability to bind the androgen receptor (AR) with non-steroidal antiandrogen moieties. Leads among these new dual-acting molecules bind to the AR and halt AR transcriptional activity at lower concentrations than clinical antiandrogens. They inhibit key isoforms of HDAC with low nanomolar potency. Fluorescent microscopy reveals varying degrees of AR nuclear localization in response to these compounds that correlates with their HDAC activity. These biological properties translate into potent anticancer activity against hormone dependent (AR+) LNCaP and to a lesser extent against hormone independent (AR−) DU145 prostate cancer, while having greatly reduced toxicity in non-cancerous cells. This illustrates that engaging multiple biological targets with a single chemical probe can achieve both potent and cell-type selective responses. PMID:24004176

  11. Histone Deacetylase Inhibitors Prolong Cardiac Repolarization through Transcriptional Mechanisms.

    PubMed

    Spence, Stan; Deurinck, Mark; Ju, Haisong; Traebert, Martin; McLean, LeeAnne; Marlowe, Jennifer; Emotte, Corinne; Tritto, Elaine; Tseng, Min; Shultz, Michael; Friedrichs, Gregory S

    2016-09-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of anticancer agents that modify gene expression by altering the acetylation status of lysine residues of histone proteins, thereby inducing transcription, cell cycle arrest, differentiation, and cell death or apoptosis of cancer cells. In the clinical setting, treatment with HDAC inhibitors has been associated with delayed cardiac repolarization and in rare instances a lethal ventricular tachyarrhythmia known as torsades de pointes. The mechanism(s) of HDAC inhibitor-induced effects on cardiac repolarization is unknown. We demonstrate that administration of structurally diverse HDAC inhibitors to dogs causes delayed but persistent increases in the heart rate corrected QT interval (QTc), an in vivo measure of cardiac repolarization, at timepoints far removed from the Tmax for parent drug and metabolites. Transcriptional profiling of ventricular myocardium from dogs treated with various HDAC inhibitors demonstrated effects on genes involved in protein trafficking, scaffolding and insertion of various ion channels into the cell membrane as well as genes for specific ion channel subunits involved in cardiac repolarization. Extensive in vitro ion channel profiling of various structural classes of HDAC inhibitors (and their major metabolites) by binding and acute patch clamp assays failed to show any consistent correlations with direct ion channel blockade. Drug-induced rescue of an intracellular trafficking-deficient mutant potassium ion channel, hERG (G601S), and decreased maturation (glycosylation) of wild-type hERG expressed by CHO cells in vitro correlated with prolongation of QTc intervals observed in vivo The results suggest that HDAC inhibitor-induced prolongation of cardiac repolarization may be mediated in part by transcriptional changes of genes required for ion channel trafficking and localization to the sarcolemma. These data have broad implications for the development of these drug classes and

  12. HDACiDB: a database for histone deacetylase inhibitors

    PubMed Central

    Murugan, Kasi; Sangeetha, Shanmugasamy; Ranjitha, Shanmugasamy; Vimala, Antony; Al-Sohaibani, Saleh; Rameshkumar, Gopal

    2015-01-01

    An histone deacetylase (HDAC) inhibitor database (HDACiDB) was constructed to enable rapid access to data relevant to the development of epigenetic modulators (HDAC inhibitors [HDACi]), helping bring precision cancer medicine a step closer. Thousands of HDACi targeting HDACs are in various stages of development and are being tested in clinical trials as monotherapy and in combination with other cancer agents. Despite the abundance of HDACi, information resources are limited. Tools for in silico experiments on specific HDACi prediction, for designing and analyzing the generated data, as well as custom-made specific tools and interactive databases, are needed. We have developed an HDACiDB that is a composite collection of HDACi and currently comprises 1,445 chemical compounds, including 419 natural and 1,026 synthetic ones having the potential to inhibit histone deacetylation. Most importantly, it will allow application of Lipinski’s rule of five drug-likeness and other physicochemical property-based screening of the inhibitors. It also provides easy access to information on their source of origin, molecular properties, drug likeness, as well as bioavailability with relevant references cited. Being the first comprehensive database on HDACi that contains all known natural and synthetic HDACi, the HDACiDB may help to improve our knowledge concerning the mechanisms of actions of available HDACi and enable us to selectively target individual HDAC isoforms and establish a new paradigm for intelligent epigenetic cancer drug design. The database is freely available on the http://hdacidb.bioinfo.au-kbc.org.in/hdacidb/website. PMID:25945037

  13. HDACiDB: a database for histone deacetylase inhibitors.

    PubMed

    Murugan, Kasi; Sangeetha, Shanmugasamy; Ranjitha, Shanmugasamy; Vimala, Antony; Al-Sohaibani, Saleh; Rameshkumar, Gopal

    2015-01-01

    An histone deacetylase (HDAC) inhibitor database (HDACiDB) was constructed to enable rapid access to data relevant to the development of epigenetic modulators (HDAC inhibitors [HDACi]), helping bring precision cancer medicine a step closer. Thousands of HDACi targeting HDACs are in various stages of development and are being tested in clinical trials as monotherapy and in combination with other cancer agents. Despite the abundance of HDACi, information resources are limited. Tools for in silico experiments on specific HDACi prediction, for designing and analyzing the generated data, as well as custom-made specific tools and interactive databases, are needed. We have developed an HDACiDB that is a composite collection of HDACi and currently comprises 1,445 chemical compounds, including 419 natural and 1,026 synthetic ones having the potential to inhibit histone deacetylation. Most importantly, it will allow application of Lipinski's rule of five drug-likeness and other physicochemical property-based screening of the inhibitors. It also provides easy access to information on their source of origin, molecular properties, drug likeness, as well as bioavailability with relevant references cited. Being the first comprehensive database on HDACi that contains all known natural and synthetic HDACi, the HDACiDB may help to improve our knowledge concerning the mechanisms of actions of available HDACi and enable us to selectively target individual HDAC isoforms and establish a new paradigm for intelligent epigenetic cancer drug design. The database is freely available on the http://hdacidb.bioinfo.au-kbc.org.in/hdacidb/website. PMID:25945037

  14. Treatment of chronic kidney diseases with histone deacetylase inhibitors

    PubMed Central

    Liu, Na; Zhuang, Shougang

    2015-01-01

    Histone deacetylases (HDACs) induce deacetylation of both histone and non-histone proteins and play a critical role in the modulation of physiological and pathological gene expression. Pharmacological inhibition of HDAC has been reported to attenuate progression of renal fibrogenesis in obstructed kidney and reduce cyst formation in polycystic kidney disease. HDAC inhibitors (HDACis) are also able to ameliorate renal lesions in diabetes nephropathy, lupus nephritis, aristolochic acid nephropathy, and transplant nephropathy. The beneficial effects of HDACis are associated with their anti-fibrosis, anti-inflammation, and immunosuppressant effects. In this review, we summarize recent advances on the treatment of various chronic kidney diseases with HDACis in pre-clinical models. PMID:25972812

  15. Functional Analysis of Histone Deacetylase 11 (HDAC11).

    PubMed

    Chen, Jie; Sahakian, Eva; Powers, John; Lienlaf, Maritza; Perez-Villarroel, Patricio; Knox, Tessa; Villagra, Alejandro

    2016-01-01

    The physiological role of histone deacetylase 11 (HDAC11), the newest member of the HDAC family, remained largely unknown until the discovery of its regulatory function in immune cells. Among them, the regulation of cytokine production by antigen-presenting cells and the modulation of the suppressive ability of myeloid-derived suppressor cells (MDSCs) (Sahakian et al. Mol Immunol 63: 579-585, 2015; Wang et al. J Immunol 186: 3986-3996, 2011; Villagra et al. Nat Immunol 10: 92-100, 2009). Our earlier data has demonstrated that HDAC11, by interacting at the chromatin level with the IL-10 promoter, downregulates il-10 transcription in both murine and human APCs in vitro and ex vivo models (Villagra et al. Nat Immunol 10: 92-100, 2009). However the role of HDAC11 in other cell types still remains unknown. Here we present several methods that can potentially be used to identify the functional role of HDAC11, assigning special attention to the evaluation of immunological parameters. PMID:27246214

  16. Histone deacetylase 6 inhibition enhances oncolytic viral replication in glioma.

    PubMed

    Nakashima, Hiroshi; Kaufmann, Johanna K; Wang, Pin-Yi; Nguyen, Tran; Speranza, Maria-Carmela; Kasai, Kazue; Okemoto, Kazuo; Otsuki, Akihiro; Nakano, Ichiro; Fernandez, Soledad; Goins, William F; Grandi, Paola; Glorioso, Joseph C; Lawler, Sean; Cripe, Timothy P; Chiocca, E Antonio

    2015-11-01

    Oncolytic viral (OV) therapy, which uses genetically engineered tumor-targeting viruses, is being increasingly used in cancer clinical trials due to the direct cytolytic effects of this treatment that appear to provoke a robust immune response against the tumor. As OVs enter tumor cells, intrinsic host defenses have the potential to hinder viral replication and spread within the tumor mass. In this report, we show that histone deacetylase 6 (HDAC6) in tumor cells appears to alter the trafficking of post-entry OVs from the nucleus toward lysosomes. In glioma cell lines and glioma-stem-like cells, HDAC6 inhibition (HDAC6i) by either pharmacologic or genetic means substantially increased replication of oncolytic herpes simplex virus type 1 (oHSV). Moreover, HDAC6i increased shuttling of post-entry oHSV to the nucleus. In addition, electron microscopic analysis revealed that post-entry oHSVs are preferentially taken up into glioma cells through the endosomal pathway rather than via fusion at the cell surface. Together, these findings illustrate a mechanism of glioma cell defense against an incoming infection by oHSV and identify possible approaches to enhance oHSV replication and subsequent lysis of tumor cells. PMID:26524593

  17. Histone deacetylase 6 inhibition enhances oncolytic viral replication in glioma

    PubMed Central

    Nakashima, Hiroshi; Kaufmann, Johanna K.; Wang, Pin-Yi; Nguyen, Tran; Speranza, Maria-Carmela; Kasai, Kazue; Okemoto, Kazuo; Otsuki, Akihiro; Nakano, Ichiro; Fernandez, Soledad; Goins, William F.; Grandi, Paola; Glorioso, Joseph C.; Lawler, Sean; Cripe, Timothy P.; Chiocca, E. Antonio

    2015-01-01

    Oncolytic viral (OV) therapy, which uses genetically engineered tumor-targeting viruses, is being increasingly used in cancer clinical trials due to the direct cytolytic effects of this treatment that appear to provoke a robust immune response against the tumor. As OVs enter tumor cells, intrinsic host defenses have the potential to hinder viral replication and spread within the tumor mass. In this report, we show that histone deacetylase 6 (HDAC6) in tumor cells appears to alter the trafficking of post-entry OVs from the nucleus toward lysosomes. In glioma cell lines and glioma-stem–like cells, HDAC6 inhibition (HDAC6i) by either pharmacologic or genetic means substantially increased replication of oncolytic herpes simplex virus type 1 (oHSV). Moreover, HDAC6i increased shuttling of post-entry oHSV to the nucleus. In addition, electron microscopic analysis revealed that post-entry oHSVs are preferentially taken up into glioma cells through the endosomal pathway rather than via fusion at the cell surface. Together, these findings illustrate a mechanism of glioma cell defense against an incoming infection by oHSV and identify possible approaches to enhance oHSV replication and subsequent lysis of tumor cells. PMID:26524593

  18. Histone Deacetylase Inhibition Restores Retinal Pigment Epithelium Function in Hyperglycemia.

    PubMed

    Desjardins, Danielle; Liu, Yueying; Crosson, Craig E; Ablonczy, Zsolt

    2016-01-01

    In diabetic individuals, macular edema is a major cause of vision loss. This condition is refractory to insulin therapy and has been attributed to metabolic memory. The retinal pigment epithelium (RPE) is central to maintaining fluid balance in the retina, and this function is compromised by the activation of advanced glycation end-product receptors (RAGE). Here we provide evidence that acute administration of the RAGE agonist, glycated-albumin (gAlb) or vascular endothelial growth factor (VEGF), increased histone deacetylase (HDAC) activity in RPE cells. The administration of the class I/II HDAC inhibitor, trichostatin-A (TSA), suppressed gAlb-induced reductions in RPE transepithelial resistance (in vitro) and fluid transport (in vivo). Systemic TSA also restored normal RPE fluid transport in rats with subchronic hyperglycemia. Both gAlb and VEGF increased HDAC activity and reduced acetyl-α-tubulin levels. Tubastatin-A, a relatively specific antagonist of HDAC6, inhibited gAlb-induced changes in RPE cell resistance. These data are consistent with the idea that RPE dysfunction following exposure to gAlb, VEGF, or hyperglycemia is associated with increased HDAC6 activity and decreased acetyl-α-tubulin. Therefore, we propose inhibiting HDAC6 in the RPE as a potential therapy for preserving normal fluid homeostasis in the hyperglycemic retina. PMID:27617745

  19. Redundant control of adipogenesis by histone deacetylases 1 and 2.

    PubMed

    Haberland, Michael; Carrer, Michele; Mokalled, Mayssa H; Montgomery, Rusty L; Olson, Eric N

    2010-05-01

    Adipocyte differentiation is a well defined process that is under the control of transcriptional activators and repressors. We show that histone deacetylase (HDAC) inhibitors efficiently block adipocyte differentiation in vitro. This effect is specific to adipogenesis, as another mesenchymal differentiation process, osteoblastogenesis, is enhanced upon HDAC inhibition. Through the systematic genetic deletion of HDAC genes in cultured mesenchymal precursor cells, we show that deletion of HDAC1 and HDAC2 leads to reduced lipid accumulation, revealing redundant and requisite roles of these class I HDACs in adipogenesis. These findings unveil a previously unrecognized role for HDACs in the control of adipogenesis. PMID:20190228

  20. Hepatic steatosis in transgenic mice overexpressing human histone deacetylase 1

    SciTech Connect

    Wang, Ai-Guo; Seo, Sang-Beom; Moon, Hyung-Bae; Shin, Hye-Jun; Kim, Dong Hoon; Kim, Jin-Man; Lee, Tae-Hoon; Kwon, Ho Jeong; Yu, Dae-Yeul . E-mail: dyyu10@kribb.re.kr; Lee, Dong-Seok . E-mail: lee10@kribb.re.kr

    2005-05-06

    It is generally thought that histone deacetylases (HDACs) play important roles in the transcriptional regulation of genes. However, little information is available concerning the specific functions of individual HDACs in disease states. In this study, two transgenic mice lines were established which harbored the human HDAC1 gene. Overexpressed HDAC1 was detected in the nuclei of transgenic liver cells, and HDAC1 enzymatic activity was significantly higher in the transgenic mice than in control littermates. The HDAC1 transgenic mice exhibited a high incidence of hepatic steatosis and nuclear pleomorphism. Molecular studies showed that HDAC1 may contribute to nuclear pleomorphism through the p53/p21 signaling pathway.

  1. Histone Deacetylase (HDAC) Inhibitors - Emerging Roles in Neuronal Memory, Learning, Synaptic Plasticity and Neural Regeneration

    PubMed Central

    Ahmad Ganai, Shabir; Ramadoss, Mahalakshmi; Mahadevan, Vijayalakshmi

    2016-01-01

    Epigenetic regulation of neuronal signalling through histone acetylation dictates transcription programs that govern neuronal memory, plasticity and learning paradigms. Histone Acetyl Transferases (HATs) and Histone Deacetylases (HDACs) are antagonistic enzymes that regulate gene expression through acetylation and deacetylation of histone proteins around which DNA is wrapped inside a eukaryotic cell nucleus. The epigenetic control of HDACs and the cellular imbalance between HATs and HDACs dictate disease states and have been implicated in muscular dystrophy, loss of memory, neurodegeneration and autistic disorders. Altering gene expression profiles through inhibition of HDACs is now emerging as a powerful technique in therapy. This review presents evolving applications of HDAC inhibitors as potential drugs in neurological research and therapy. Mechanisms that govern their expression profiles in neuronal signalling, plasticity and learning will be covered. Promising and exciting possibilities of HDAC inhibitors in memory formation, fear conditioning, ischemic stroke and neural regeneration have been detailed. PMID:26487502

  2. Histone Deacetylase (HDAC) Inhibitors - emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration.

    PubMed

    Ganai, Shabir Ahmad; Ramadoss, Mahalakshmi; Mahadevan, Vijayalakshmi

    2016-01-01

    Epigenetic regulation of neuronal signalling through histone acetylation dictates transcription programs that govern neuronal memory, plasticity and learning paradigms. Histone Acetyl Transferases (HATs) and Histone Deacetylases (HDACs) are antagonistic enzymes that regulate gene expression through acetylation and deacetylation of histone proteins around which DNA is wrapped inside a eukaryotic cell nucleus. The epigenetic control of HDACs and the cellular imbalance between HATs and HDACs dictate disease states and have been implicated in muscular dystrophy, loss of memory, neurodegeneration and autistic disorders. Altering gene expression profiles through inhibition of HDACs is now emerging as a powerful technique in therapy. This review presents evolving applications of HDAC inhibitors as potential drugs in neurological research and therapy. Mechanisms that govern their expression profiles in neuronal signalling, plasticity and learning will be covered. Promising and exciting possibilities of HDAC inhibitors in memory formation, fear conditioning, ischemic stroke and neural regeneration have been detailed. PMID:26487502

  3. Histone deacetylase inhibitors: possible implications for neurodegenerative disorders.

    PubMed

    Hahnen, Eric; Hauke, Jan; Tränkle, Christian; Eyüpoglu, Ilker Y; Wirth, Brunhilde; Blümcke, Ingmar

    2008-02-01

    During the past six years numerous studies identified histone deacetylase (HDAC) inhibitors as candidate drugs for the treatment of neurodegenerative disorders. Two major neuroprotective mechanisms of HDAC inhibitors have been identified, namely the transcriptional activation of disease-modifying genes and the correction of perturbations in histone acetylation homeostasis, which have been shown to be intimately involved in the neurodegenerative pathomechanisms of Huntington's, Parkinson's and Kennedy disease, amyotropic lateral sclerosis, Rubinstein-Taybi syndrome as well as stroke. Based on the promising in vitro and in vivo analyses, clinical trials have been initiated to evaluate the safety and efficacy of HDAC inhibitors for the treatment of devastating diseases such as Huntington's disease, amyotropic lateral sclerosis and spinal muscular atrophy. Here, the authors summarize and discuss the findings on the emerging field of epigenetic therapy strategies in neurodegenerative disorders. PMID:18230051

  4. Chemical tools for probing histone deacetylase (HDAC) activity.

    PubMed

    Minoshima, Masafumi; Kikuchi, Kazuya

    2015-01-01

    Histone deacetylases (HDACs) enzymes are responsible for removing epigenetic markers on histone proteins, which results in chromatin inactivation and gene repression. An evaluation of HDAC activity is essential for not only determining the physiological function of HDACs, but also for developing HDAC-targeting drugs. This review focuses on the chemical tools used to detect HDAC activity. We highlight activity-based probes and positron emission tomography probes based on the chemical structure of the inhibitors. We also summarize fluorogenic probes used in single-step methods for HDAC detection. These fluorogenic probes are designed based on the nucleophilicity of the amino group, aggregation via electrostatic interactions, and changes in the DNA binding properties. These fluorogenic systems may enable facile and rapid screening to evaluate HDAC inhibitors, which will contribute to the development of epigenetic drugs. PMID:25864671

  5. The Therapeutic Potential of AN-7, a Novel Histone Deacetylase Inhibitor, for Treatment of Mycosis Fungoides/Sezary Syndrome Alone or with Doxorubicin

    PubMed Central

    Goldfeiz, Neta; Rephaeli, Ada; Nudelman, Abraham; Weitman, Michal; Tarasenko, Nataly; Gorovitz, Batia; Maron, Leah; Yehezkel, Shiran; Amitay-Laish, Iris; Lubin, Ido; Hodak, Emmilia

    2016-01-01

    The 2 histone deacetylase inhibitors (HDACIs) approved for the treatment of cutaneous T-cell lymphoma (CTCL) including mycosis fungoides/sezary syndrome (MF/SS), suberoylanilide hydroxamic acid (SAHA) and romidepsin, are associated with low rates of overall response and high rates of adverse effects. Data regarding combination treatments with HDACIs is sparse. Butyroyloxymethyl diethylphosphate (AN-7) is a novel HDACI, which was found to have selective anticancer activity in several cell lines and animal models. The aim of this study was to compare the anticancer effects of AN-7 and SAHA, either alone or combined with doxorubicin, on MF/SS cell lines and peripheral blood lymphocytes (PBL) from patients with Sezary syndrome (SPBL). MyLa cells, Hut78 cells, SPBL, and PBL from healthy normal individuals (NPBL) were exposed to the test drugs, and the findings were analyzed by a viability assay, an apoptosis assay, and Western blot. AN-7 was more selectively toxic to MyLa cells, Hut78 cells, and SPBL (relative to NPBL) than SAHA and also acted more rapidly. Both drugs induced apoptosis in MF/SS cell lines, SAHA had a greater effect on MyLa cell line, while AN-7 induced greater apoptosis in SPBL; both caused an accumulation of acetylated histone H3, but AN-7 was associated with earlier kinetics; and both caused a downregulation of the HDAC1 protein in MF/SS cell lines. AN-7 acted synergistically with doxorubicin in both MF/SS cell lines and SPBL, and antagonistically with doxorubicin in NPBL. By contrast, SAHA acted antagonistically with doxorubicin on MF/SS cell lines, SPBL, and NPBL, leaving <50% viable cells. In conclusion, AN-7 holds promise as a therapeutic agent in MF/SS and has several advantages over SAHA. Our data provide a rationale for combining AN-7, but not SAHA, with doxorubicin to induce the cell death in MF/SS. PMID:26752418

  6. Histone deacetylases in fungi: novel members, new facts.

    PubMed

    Trojer, Patrick; Brandtner, Eva M; Brosch, Gerald; Loidl, Peter; Galehr, Johannes; Linzmaier, Roland; Haas, Hubertus; Mair, Karin; Tribus, Martin; Graessle, Stefan

    2003-07-15

    Acetylation is the most prominent modification on core histones that strongly affects nuclear processes such as DNA replication, DNA repair and transcription. Enzymes responsible for the dynamic equilibrium of histone acetylation are histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this paper we describe the identification of novel HDACs from the filamentous fungi Aspergillus nidulans and the maize pathogen Cochliobolus carbonum. Two of the enzymes are homologs of Saccharomyces cerevisiae HOS3, an enzyme that has not been identified outside of the established yeast systems until now. One of these homologs, HosB, showed intrinsic HDAC activity and remarkable resistance against HDAC inhibitors like trichostatin A (TSA) when recombinant expressed in an Escherichia coli host system. Phylo genetic analysis revealed that HosB, together with other fungal HOS3 orthologs, is a member of a separate group within the classical HDACs. Immunological investigations with partially purified HDAC activities of Aspergillus showed that all classical enzymes are part of high molecular weight complexes and that a TSA sensitive class 2 HDAC constitutes the major part of total HDAC activity of the fungus. However, further biochemical analysis also revealed an NAD(+)-dependent activity that could be separated from the other activities by different types of chromatography and obviously represents an enzyme of the sirtuin class. PMID:12853613

  7. Electrocardiographic effects of class 1 selective histone deacetylase inhibitor romidepsin

    PubMed Central

    Sager, Philip T; Balser, Barbara; Wolfson, Julie; Nichols, Jean; Pilot, Richard; Jones, Suzanne; Burris, Howard A

    2015-01-01

    Romidepsin is a histone deacetylase inhibitor approved by the FDA for the treatment of patients with cutaneous or peripheral T-cell lymphoma who have received prior systemic therapy. The objective of this analysis was to evaluate the potential QTc effects of romidepsin. Patients with advanced malignancy received 4-h infusions of 14 mg/m2 romidepsin on days 1, 8, and 15 of a 28-day cycle. In cycle 2, a subset of patients received 1-h infusions of 8–12 mg/m2 romidepsin. Patients were administered antiemetics before each romidepsin dose and electrolyte supplementation as needed. Electrocardiogram readings were performed prior to antiemetic administration, prior to romidepsin administration, and at specified time points over the subsequent 24 h. Romidepsin exposure and heart rate were also assessed. In the electrocardiogram-evaluable population, 26 patients received romidepsin at 14 mg/m2 over 4 h. The maximum mean increases from the preantiemetic baseline for QTcF and heart rate were 10.1 msec (upper 90% CI, 14.5 msec) and 18.2 beats per minute, respectively. No patient in this study had an absolute QTcF value >450 msec and only one patient had an increase from the preantiemetic baseline of >60 msec. There was a mild reduction in the PR interval and no meaningful changes in the QRS interval. Despite the use of QT-prolonging antiemetics, treatment with romidepsin did not markedly prolong the QTc interval through 24 h. Increases in calculated QTc may have been exaggerated as a consequence of transient increases in heart rate. PMID:25914207

  8. Identification and characterization of histone deacetylases in tomato (Solanum lycopersicum)

    PubMed Central

    Zhao, Linmao; Lu, Jingxia; Zhang, Jianxia; Wu, Pei-Ying; Yang, Songguang; Wu, Keqiang

    2015-01-01

    Histone acetylation and deacetylation at the N-terminus of histone tails play crucial roles in the regulation of eukaryotic gene activity. Histone acetylation and deacetylation are catalyzed by histone acetyltransferases and histone deacetylases (HDACs), respectively. A growing number of studies have demonstrated the importance of histone deacetylation/acetylation on genome stability, transcriptional regulation, development and response to stress in Arabidopsis. However, the biological functions of HDACs in tomato have not been investigated previously. Fifteen HDACs identified from tomato (Solanum lycopersicum) can be grouped into RPD3/HDA1, SIR2 and HD2 families based on phylogenetic analysis. Meanwhile, 10 members of the RPD3/HDA1 family can be further subdivided into four groups, namely Class I, Class II, Class III, and Class IV. High similarities of protein sequences and conserved domains were identified among SlHDACs and their homologs in Arabidopsis. Most SlHDACs were expressed in all tissues examined with different transcript abundance. Transient expression in Arabidopsis protoplasts showed that SlHDA8, SlHDA1, SlHDA5, SlSRT1 and members of the HD2 family were localized to the nucleus, whereas SlHDA3 and SlHDA4 were localized in both the cytoplasm and nucleus. The difference in the expression patterns and subcellular localization of SlHDACs suggest that they may play distinct functions in tomato. Furthermore, we found that three members of the RPD3/HDA1 family, SlHDA1, SIHDA3 and SlHDA4, interacted with TAG1 (TOMATO AGAMOUS1) and TM29 (TOMATO MADS BOX29), two MADS-box proteins associated with tomato reproductive development, indicating that these HDACs may be involved in gene regulation in reproductive development. PMID:25610445

  9. Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).

    PubMed

    Carrillo, Angela K; Guiguemde, W Armand; Guy, R Kiplin

    2015-08-15

    Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs. PMID:25637120

  10. The Role of Dietary Histone Deacetylases (HDACs) Inhibitors in Health and Disease

    PubMed Central

    Bassett, Shalome A.; Barnett, Matthew P. G.

    2014-01-01

    Modification of the histone proteins associated with DNA is an important process in the epigenetic regulation of DNA structure and function. There are several known modifications to histones, including methylation, acetylation, and phosphorylation, and a range of factors influence each of these. Histone deacetylases (HDACs) remove the acetyl group from lysine residues within a range of proteins, including transcription factors and histones. Whilst this means that their influence on cellular processes is more complex and far-reaching than histone modifications alone, their predominant function appears to relate to histones; through deacetylation of lysine residues they can influence expression of genes encoded by DNA linked to the histone molecule. HDAC inhibitors in turn regulate the activity of HDACs, and have been widely used as therapeutics in psychiatry and neurology, in which a number of adverse outcomes are associated with aberrant HDAC function. More recently, dietary HDAC inhibitors have been shown to have a regulatory effect similar to that of pharmacological HDAC inhibitors without the possible side-effects. Here, we discuss a number of dietary HDAC inhibitors, and how they may have therapeutic potential in the context of a whole food. PMID:25322459

  11. Histone Deacetylases and Their Inhibition in Candida Species.

    PubMed

    Garnaud, Cécile; Champleboux, Morgane; Maubon, Danièle; Cornet, Muriel; Govin, Jérôme

    2016-01-01

    Fungi are generally benign members of the human mucosal flora or live as saprophytes in the environment. However, they can become pathogenic, leading to invasive and life threatening infections in vulnerable patients. These invasive fungal infections are regarded as a major public health problem on a similar scale to tuberculosis or malaria. Current treatment for these infections is based on only four available drug classes. This limited therapeutic arsenal and the emergence of drug-resistant strains are a matter of concern due to the growing number of patients to be treated, and new therapeutic strategies are urgently needed. Adaptation of fungi to drug pressure involves transcriptional regulation, in which chromatin dynamics and histone modifications play a major role. Histone deacetylases (HDACs) remove acetyl groups from histones and actively participate in controlling stress responses. HDAC inhibition has been shown to limit fungal development, virulence, biofilm formation, and dissemination in the infected host, while also improving the efficacy of existing antifungal drugs toward Candida spp. In this article, we review the functional roles of HDACs and the biological effects of HDAC inhibitors on Candida spp., highlighting the correlations between their pathogenic effects in vitro and in vivo. We focus on how HDAC inhibitors could be used to treat invasive candidiasis while also reviewing recent developments in their clinical evaluation. PMID:27547205

  12. Insights into neuroepigenetics through human histone deacetylase PET imaging.

    PubMed

    Wey, Hsiao-Ying; Gilbert, Tonya M; Zürcher, Nicole R; She, Angela; Bhanot, Anisha; Taillon, Brendan D; Schroeder, Fredrick A; Wang, Changing; Haggarty, Stephen J; Hooker, Jacob M

    2016-08-10

    Epigenetic dysfunction is implicated in many neurological and psychiatric diseases, including Alzheimer's disease and schizophrenia. Consequently, histone deacetylases (HDACs) are being aggressively pursued as therapeutic targets. However, a fundamental knowledge gap exists regarding the expression and distribution of HDACs in healthy individuals for comparison to disease states. Here, we report the first-in-human evaluation of neuroepigenetic regulation in vivo. Using positron emission tomography with [(11)C]Martinostat, an imaging probe selective for class I HDACs (isoforms 1, 2, and 3), we found that HDAC expression is higher in cortical gray matter than in white matter, with conserved regional distribution patterns within and between healthy individuals. Among gray matter regions, HDAC expression was lowest in the hippocampus and amygdala. Through biochemical profiling of postmortem human brain tissue, we confirmed that [(11)C]Martinostat selectively binds HDAC isoforms 1, 2, and 3, the HDAC subtypes most implicated in regulating neuroplasticity and cognitive function. In human stem cell-derived neural progenitor cells, pharmacologic-level doses of Martinostat induced changes in genes closely associated with synaptic plasticity, including BDNF (brain-derived neurotrophic factor) and SYP (synaptophysin), as well as genes implicated in neurodegeneration, including GRN (progranulin), at the transcript level, in concert with increased acetylation at both histone H3 lysine 9 and histone H4 lysine 12. This study quantifies HDAC expression in the living human brain and provides the foundation for gaining unprecedented in vivo epigenetic information in health and disease. PMID:27510902

  13. Current evidence for histone deacetylase inhibitors in pancreatic cancer

    PubMed Central

    Koutsounas, Ioannis; Giaginis, Constantinos; Patsouris, Efstratios; Theocharis, Stamatios

    2013-01-01

    Pancreatic cancer is one of the most aggressive human cancers, with more than 200 000 deaths worldwide every year. Despite recent efforts, conventional treatment approaches, such as surgery and classic chemotherapy, have only slightly improved patient outcomes. More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm. Among new agents, histone deacetylase inhibitors (HDACIs) are now being tested. HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression, apoptosis, cell cycle progression and angiogenesis. HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines. In the present review, the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro, as well as their antiproliferative effects in animal models are presented. HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor effects, at well-tolerated doses. PMID:23430136

  14. Histone Deacetylases and Their Inhibition in Candida Species

    PubMed Central

    Garnaud, Cécile; Champleboux, Morgane; Maubon, Danièle; Cornet, Muriel; Govin, Jérôme

    2016-01-01

    Fungi are generally benign members of the human mucosal flora or live as saprophytes in the environment. However, they can become pathogenic, leading to invasive and life threatening infections in vulnerable patients. These invasive fungal infections are regarded as a major public health problem on a similar scale to tuberculosis or malaria. Current treatment for these infections is based on only four available drug classes. This limited therapeutic arsenal and the emergence of drug-resistant strains are a matter of concern due to the growing number of patients to be treated, and new therapeutic strategies are urgently needed. Adaptation of fungi to drug pressure involves transcriptional regulation, in which chromatin dynamics and histone modifications play a major role. Histone deacetylases (HDACs) remove acetyl groups from histones and actively participate in controlling stress responses. HDAC inhibition has been shown to limit fungal development, virulence, biofilm formation, and dissemination in the infected host, while also improving the efficacy of existing antifungal drugs toward Candida spp. In this article, we review the functional roles of HDACs and the biological effects of HDAC inhibitors on Candida spp., highlighting the correlations between their pathogenic effects in vitro and in vivo. We focus on how HDAC inhibitors could be used to treat invasive candidiasis while also reviewing recent developments in their clinical evaluation. PMID:27547205

  15. Tetrahydroisoquinolines as novel histone deacetylase inhibitors for treatment of cancer.

    PubMed

    Chen, Danqi; Shen, Aijun; Fang, Guanghua; Liu, Hongchun; Zhang, Minmin; Tang, Shuai; Xiong, Bing; Ma, Lanping; Geng, Meiyu; Shen, Jingkang

    2016-01-01

    Histone acetylation is a critical process in the regulation of chromatin structure and gene expression. Histone deacetylases (HDACs) remove the acetyl group, leading to chromatin condensation and transcriptional repression. HDAC inhibitors are considered a new class of anticancer agents and have been shown to alter gene transcription and exert antitumor effects. This paper describes our work on the structural determination and structure-activity relationship (SAR) optimization of tetrahydroisoquinoline compounds as HDAC inhibitors. These compounds were tested for their ability to inhibit HDAC 1, 3, 6 and for their ability to inhibit the proliferation of a panel of cancer cell lines. Among these, compound 82 showed the greatest inhibitory activity toward HDAC 1, 3, 6 and strongly inhibited growth of the cancer cell lines, with results clearly superior to those of the reference compound, vorinostat (SAHA). Compound 82 increased the acetylation of histones H3, H4 and tubulin in a concentration-dependent manner, suggesting that it is a broad inhibitor of HDACs. PMID:26904403

  16. Role of histone acetyltransferases and histone deacetylases in adipocyte differentiation and adipogenesis.

    PubMed

    Zhou, Yuanfei; Peng, Jian; Jiang, Siwen

    2014-04-01

    Adipogenesis is a complex process strictly regulated by a well-established cascade that has been thoroughly studied in the last two decades. This process is governed by complex regulatory networks that involve the activation/inhibition of multiple functional genes, and is controlled by histone-modifying enzymes. Among such modification enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs) play important roles in the transcriptional regulation and post-translational modification of protein acetylation. HATs and HDACs have been shown to respond to signals that regulate cell differentiation, participate in the regulation of protein acetylation, mediate transcription and post-translation modifications, and directly acetylate/deacetylate various transcription factors and regulatory proteins. In this paper, we review the role of HATs and HDACs in white and brown adipocyte differentiation and adipogenesis, to expand our knowledge on fat formation and adipose tissue biology. PMID:24810880

  17. [Histone deacetylase inhibitors: new synergistic third-line option in multiple myeloma].

    PubMed

    Stegmann, Danielle A

    2016-04-01

    Despite advances in drug therapy of the orphan disease multiple myeloma, patients relapse or become refractory to first-line therapy, and the disease remains incurable. Therefore, histone deacetylase inhibitors have emerged as a new class of anti-myeloma drugs, with synergistic results on progression free survival when given in combination to current first-line therapy. Histone deacetylase inhibitors influence gene expression of target genes. Based on results of an extensive multicenter phase III trial, panobinostat was approved by the FDA in February 2015 as the first histone deacetylase inhibitor for the treatment of multiple myeloma. In Europe, panobinostat received marketing authorization by August 2015. PMID:27209894

  18. Histone Deacetylases in Skeletal Development and Bone Mass Maintenance

    PubMed Central

    McGee-Lawrence, Meghan E.; Westendorf, Jennifer J.

    2011-01-01

    The skeleton is a multifunctional and regenerative organ. Dynamic activities within the bone microenvironment necessitate and instigate rapid and temporal changes in gene expression within the cells (osteoclasts, osteoblasts, and osteocytes) responsible for skeletal maintenance. Regulation of gene expression is controlled, in part, by histone deacetylases (Hdacs), which are intracellular enzymes that directly affect chromatin structure and transcription factor activity. Key roles for several Hdacs in bone development and biology have been elucidated though in vitro and in vivo models. Recent findings suggest that clinical usage of small molecule Hdac inhibitors for conditions like epilepsy, bipolar disorder, cancer, and a multitude of other ailments may have unintended effects on bone cell populations. Here we review the progress that has been made in the last decade in understanding how Hdacs contribute to bone development and maintenance. PMID:21185361

  19. Histone deacetylase inhibitors disrupt the mitotic spindle assembly checkpoint by targeting histone and nonhistone proteins.

    PubMed

    Gabrielli, Brian; Brown, Mellissa

    2012-01-01

    Histone deacetylase inhibitors exhibit pleiotropic effects on cell functions, both in vivo and in vitro. One of the more dramatic effects of these drugs is their ability to disrupt normal mitotic division, which is a significant contributor to the anticancer properties of these drugs. The most important feature of the disrupted mitosis is that drug treatment overcomes the mitotic spindle assembly checkpoint and drives mitotic slippage, but in a manner that triggers apoptosis. The mechanism by which histone deacetylase inhibitors affect mitosis is now becoming clearer through the identification of a number of chromatin and nonchromatin protein targets that are critical to the regulation of normal mitotic progression and cell division. These proteins are directly regulated by acetylation and deacetylation, or in some cases indirectly through the acetylation of essential partner proteins. There appears to be little contribution from deacetylase inhibitor-induced transcriptional changes to the mitotic effects of these drugs. The overall mitotic phenotype of drug treatment appears to be the sum of these disrupted mechanisms. PMID:23088867

  20. Inhibition of histone deacetylase as a new mechanism of teratogenesis.

    PubMed

    Menegola, Elena; Di Renzo, Francesca; Broccia, Maria Luisa; Giavini, Erminio

    2006-12-01

    Histone deacetylases (HDACs) are nuclear and cytoplasmic enzymes that deacetylate a number of substrates, of which histones are the best known and described in the literature. HDACs are present in eukaryotic and bacteria cells, and are fundamental for a number of cellular functions, including correct gene expression. Surprisingly, only up to 20% of the whole genome is controlled by HDACs, but key processes for survival, proliferation, and differentiation have been strictly linked to HDAC enzyme functioning. The use of HDAC inhibitors (HDACi) has been proposed for the treatment of neoplastic diseases. Their effectiveness has been suggested for a number of liquid and solid tumors, particularly acute promyelocytic leukemia (APL). The role of HDACs in embryo development is currently under investigation. Published data indicate knockout phenotype analysis to be of particular interest, in which a number of HDACs play a key role during development. Little data have been published on the effects of HDACi on embryonic development, although for valproic acid (VPA), literature from the 1980s described its teratogenic effects in experimental animals and humans. To date, all tested HDACi have shown teratogenic effects similar to those described for VPA when tested in zebrafish, Xenopus laevis, and mice. HDACs were also able to alter embryo development in invertebrates and plants. A model, similar to that proposed in APL, involving retinoic acid receptors (RAR) and tissue specific Hox gene expression, is suggested to explain the HDAC effects on embryo development. PMID:17315247

  1. Histone deacetylase 5 regulates the inflammatory response of macrophages

    PubMed Central

    Poralla, Lukas; Stroh, Thorsten; Erben, Ulrike; Sittig, Marie; Liebig, Sven; Siegmund, Britta; Glauben, Rainer

    2015-01-01

    Modifying the chromatin structure and interacting with non-histone proteins, histone deacetylases (HDAC) are involved in vital cellular processes at different levels. We here specifically investigated the direct effects of HDAC5 in macrophage activation in response to bacterial or cytokine stimuli. Using murine and human macrophage cell lines, we studied the expression profile and the immunological function of HDAC5 at transcription and protein level in over-expression as well as RNA interference experiments. Toll-like receptor-mediated stimulation of murine RAW264.7 cells significantly reduced HDAC5 mRNA within 7 hrs but presented baseline levels after 24 hrs, a mechanism that was also found for Interferon-γ treatment. If treated with lipopolysaccharide, RAW264.7 cells transfected for over-expression only of full-length but not of mutant HDAC5, significantly elevated secretion of tumour necrosis factor α and of the monocyte chemotactic protein-1. These effects were accompanied by increased nuclear factor-κB activity. Accordingly, knock down of HDAC5-mRNA expression using specific siRNA significantly reduced the production of these cytokines in RAW264.7 or human U937 cells. Taken together, our results suggest a strong regulatory function of HDAC5 in the pro-inflammatory response of macrophages. PMID:26059794

  2. Histone deacetylase inhibitors enhance phosphorylation of histone H2AX after ionizing radiation

    SciTech Connect

    Zhang Yubin; Adachi, Masaaki . E-mail: adachi@sapmed.ac.jp; Zou Huichao; Hareyama, Masato; Imai, Kohzoh; Shinomura, Yasuhisa

    2006-07-01

    Purpose Histone deacetylase (HDAC) inhibitors are believed to be promising radiosensitizers. To explore their effects on ionizing radiation (IR), we examined whether the HDAC inhibitors m-carboxycinnamic acid bis-hydroxamide (CBHA) and depsipeptide FK228 affect H2AX phosphorylation ({gamma}-H2AX), a landmark of DNA double-strand breaks after IR exposure. Methods and Materials We evaluated the effects of the HDAC inhibitors on clonogenic assay in human lung carcinoma A549 cells and progression of A549 xenograft tumors. IR-induced DNA damage was evaluated by histone {gamma}-H2AX. Histone hyperacetylation was induced by overexpression of histone acetyltransferase p300 and evaluated by Western blots. Results M-carboxycinnamic acid bishydroxyamide pretreatment radiosensitized A549 cells and strongly inhibited A549 xenograft tumor progression. CBHA and FK228, but not 5-fluorouracil, enhanced IR-induced {gamma}-H2AX in A549 and other cancer cell lines. Overexpression of p300 similarly augmented IR-induced {gamma}-H2AX. Conclusion The results of this study suggest that HDAC inhibitors enhance IR-induced {gamma}-H2AX, most likely through histone hyperacetylation, and radiosensitize various cancers.

  3. Role of histone deacetylases in pancreas: Implications for pathogenesis and therapy

    PubMed Central

    Klieser, Eckhard; Swierczynski, Stefan; Mayr, Christian; Schmidt, Johanna; Neureiter, Daniel; Kiesslich, Tobias; Illig, Romana

    2015-01-01

    In the last years, our knowledge of the pathogenesis in acute and chronic pancreatitis (AP/CP) as well as in pancreatic cancerogenesis has significantly diversified. Nevertheless, the medicinal therapeutic options are still limited and therapeutic success and patient outcome are poor. Epigenetic deregulation of gene expression is known to contribute to development and progression of AP and CP as well as of pancreatic cancer. Therefore, the selective inhibition of aberrantly active epigenetic regulators can be an effective option for future therapies. Histone deacetylases (HDACs) are enzymes that remove an acetyl group from histone tails, thereby causing chromatin compaction and repression of transcription. In this review we present an overview of the currently available literature addressing the role of HDACs in the pancreas and in pancreatic diseases. In pancreatic cancerogenesis, HDACs play a role in the important process of epithelial-mesenchymal-transition, ubiquitin-proteasome pathway and, hypoxia-inducible-factor-1-angiogenesis. Finally, we focus on HDACs as potential therapeutic targets by summarizing currently available histone deacetylase inhibitors. PMID:26691388

  4. Roles and post-translational regulation of cardiac class IIa histone deacetylase isoforms.

    PubMed

    Weeks, Kate L; Avkiran, Metin

    2015-04-15

    Cardiomyocyte hypertrophy is an integral component of pathological cardiac remodelling in response to mechanical and chemical stresses in settings such as chronic hypertension or myocardial infarction. For hypertrophy to ensue, the pertinent mechanical and chemical signals need to be transmitted from membrane sensors (such as receptors for neurohormonal mediators) to the cardiomyocyte nucleus, leading to altered transcription of the genes that regulate cell growth. In recent years, nuclear histone deacetylases (HDACs) have attracted considerable attention as signal-responsive, distal regulators of the transcriptional reprogramming that in turn precipitates cardiomyocyte hypertrophy, with particular focus on the role of members of the class IIa family, such as HDAC4 and HDAC5. These histone deacetylase isoforms appear to repress cardiomyocyte hypertrophy through mechanisms that involve protein interactions in the cardiomyocyte nucleus, particularly with pro-hypertrophic transcription factors, rather than via histone deacetylation. In contrast, evidence indicates that class I HDACs promote cardiomyocyte hypertrophy through mechanisms that are dependent on their enzymatic activity and thus sensitive to pharmacological HDAC inhibitors. Although considerable progress has been made in understanding the roles of post-translational modifications (PTMs) such as phosphorylation, oxidation and proteolytic cleavage in regulating class IIa HDAC localisation and function, more work is required to explore the contributions of other PTMs, such as ubiquitination and sumoylation, as well as potential cross-regulatory interactions between distinct PTMs and between class IIa and class I HDAC isoforms. PMID:25362149

  5. Roles and post-translational regulation of cardiac class IIa histone deacetylase isoforms

    PubMed Central

    Weeks, Kate L; Avkiran, Metin

    2015-01-01

    Cardiomyocyte hypertrophy is an integral component of pathological cardiac remodelling in response to mechanical and chemical stresses in settings such as chronic hypertension or myocardial infarction. For hypertrophy to ensue, the pertinent mechanical and chemical signals need to be transmitted from membrane sensors (such as receptors for neurohormonal mediators) to the cardiomyocyte nucleus, leading to altered transcription of the genes that regulate cell growth. In recent years, nuclear histone deacetylases (HDACs) have attracted considerable attention as signal-responsive, distal regulators of the transcriptional reprogramming that in turn precipitates cardiomyocyte hypertrophy, with particular focus on the role of members of the class IIa family, such as HDAC4 and HDAC5. These histone deacetylase isoforms appear to repress cardiomyocyte hypertrophy through mechanisms that involve protein interactions in the cardiomyocyte nucleus, particularly with pro-hypertrophic transcription factors, rather than via histone deacetylation. In contrast, evidence indicates that class I HDACs promote cardiomyocyte hypertrophy through mechanisms that are dependent on their enzymatic activity and thus sensitive to pharmacological HDAC inhibitors. Although considerable progress has been made in understanding the roles of post-translational modifications (PTMs) such as phosphorylation, oxidation and proteolytic cleavage in regulating class IIa HDAC localisation and function, more work is required to explore the contributions of other PTMs, such as ubiquitination and sumoylation, as well as potential cross-regulatory interactions between distinct PTMs and between class IIa and class I HDAC isoforms. PMID:25362149

  6. Fourier transform infrared microspectroscopy identifies protein propionylation in histone deacetylase inhibitor treated glioma cells.

    PubMed

    Singh, Bhawana; Boopathy, Sivaraman; Somasundaram, Kumaravel; Umapathy, Siva

    2012-03-01

    Histone deacetylase inhibitors (HDIs) have attracted considerable attention as potential drug molecules in tumour biology. In order to optimise chemotherapy, it is important to understand the mechanisms of regulation of histone deacetylase (HDAC) enzymes and modifications brought by various HDIs. In the present study, we have employed Fourier transform infrared microspectroscopy (FT-IRMS) to evaluate modifications in cellular macromolecules subsequent to treatment with various HDIs. In addition to CH(3) (methyl) stretching bands at 2872 and 2960 cm(-1) , which arises due to acetylation, we also found major changes in bands at 2851 and 2922 cm(-1) , which originates from stretching vibrations of CH(2) (methylene) groups, in valproic acid treated cells. We further demonstrate that the changes in CH(2) stretching are concentration-dependent and also induced by several other HDIs. Recently, HDIs have been shown to induce propionylation besides acetylation [1]. Since propionylation involves CH(2) groups, we hypothesized that CH(2) vibrational frequency changes seen in HDI treated cells could arise due to propionylation. As verification, pre-treatment of cells with propionyl CoA synthetase inhibitor resulted in loss of CH(2) vibrational changes in histones, purified from valproic acid treated cells. This was further proved by western blot using propionyl-lysine specific antibody. Thus we demonstrate for the first time that propionylation could be monitored by studying CH(2) stretching using IR spectroscopy and further provide a platform for monitoring HDI induced multiple changes in cells. PMID:22259119

  7. Identification of new quinic acid derivatives as histone deacetylase inhibitors by fluorescence-based cellular assay.

    PubMed

    Son, Dohyun; Kim, Chung Sub; Lee, Kang Ro; Park, Hyun-Ju

    2016-05-01

    A fluorescence-based cellular assay system was established to identify potential epigenetic modulator ligands. This assay method is to detect the de-repression of an EGFP reporter in cancer cells by the treatment of HDAC (histone deacetylase) or DNMT (DNA methyltransferase) inhibitor. Using this system, we conducted a preliminary screening of in-house natural product library containing extracts and pure compounds, and identified several active compounds. Among them, novel quinic acid derivatives were recognized as excellent HDAC inhibitors by both enzymatic and cell-based HDAC assays. PMID:26996372

  8. Histone deacetylase 3 (HDAC 3) as emerging drug target in NF-κB-mediated inflammation

    PubMed Central

    Leus, Niek G.J.; Zwinderman, Martijn R.H.; Dekker, Frank J.

    2016-01-01

    Activation of inflammatory gene expression is regulated, among other factors, by post-translational modifications of histone proteins. The most investigated type of histone modifications are lysine acetylations. Histone deacetylases (HDACs) remove acetylations from lysines, thereby influencing (inflammatory) gene expression. Intriguingly, apart from histones, HDACs also target non-histone proteins. The nuclear factor κB (NF-κB) pathway is an important regulator in the expression of numerous inflammatory genes, and acetylation plays a crucial role in regulating its responses. Several studies have shed more light on the role of HDAC 1-3 in inflammation with a particular pro-inflammatory role for HDAC 3. Nevertheless, the HDAC-NF-κB interactions in inflammatory signalling have not been fully understood. An important challenge in targeting the regulatory role of HDACs in the NF-κB pathway is the development of highly potent small molecules that selectively target HDAC iso-enzymes. This review focuses on the role of HDAC 3 in (NF-κB-mediated) inflammation and NF-κB lysine acetylation. In addition, we address the application of frequently used small molecule HDAC inhibitors as an approach to attenuate inflammatory responses, and their potential as novel therapeutics. Finally, recent progress and future directions in medicinal chemistry efforts aimed at HDAC 3-selective inhibitors are discussed. PMID:27371876

  9. Histone deacetylase expression patterns in developing murine optic nerve

    PubMed Central

    2014-01-01

    Background Histone deacetylases (HDACs) play important roles in glial cell development and in disease states within multiple regions of the central nervous system. However, little is known about HDAC expression or function within the optic nerve. As a first step in understanding the role of HDACs in optic nerve, this study examines the spatio-temporal expression patterns of methylated histone 3 (K9), acetylated histone 3 (K18), and HDACs 1–6 and 8–11 in the developing murine optic nerve head. Results Using RT-qPCR, western blot and immunofluorescence, three stages were analyzed: embryonic day 16 (E16), when astrocyte precursors are found in the optic stalk, postnatal day 5 (P5), when immature astrocytes and oligodendrocytes are found throughout the optic nerve, and P30, when optic nerve astrocytes and oligodendrocytes are mature. Acetylated and methylated histone H3 immunoreactivity was co-localized in the nuclei of most SOX2 positive glia within the optic nerve head and adjacent optic nerve at all developmental stages. HDACs 1–11 were expressed in the optic nerve glial cells at all three stages of optic nerve development in the mouse, but showed temporal differences in overall levels and subcellular localization. HDACs 1 and 2 were predominantly nuclear throughout optic nerve development and glial cell maturation. HDACs 3, 5, 6, 8, and 11 were predominantly cytoplasmic, but showed nuclear localization in at least one stage of optic nerve development. HDACs 4, 9 and10 were predominantly cytoplasmic, with little to no nuclear expression at any time during the developmental stages examined. Conclusions Our results showing that HDACs 1, 2, 3, 5, 6, 8, and 11 were each localized to the nuclei of SOX2 positive glia at some stages of optic nerve development and maturation and extend previous reports of HDAC expression in the aging optic nerve. These HDACs are candidates for further research to understand how chromatin remodeling through acetylation, deacetylation

  10. Supramolecular Affinity Labeling of Histone Peptides Containing Trimethyllysine and Its Application to Histone Deacetylase Assays.

    PubMed

    Gober, Isaiah N; Waters, Marcey L

    2016-08-01

    Lysine methylation is an important histone post-translational modification (PTM) for manipulating chromatin structure and regulating gene expression, and its dysregulation is associated with various diseases including many cancers. While characterization of Lys methylation has seen improvements over the past decade due to advances in proteomic mass spectrometry and methods involving antibodies, chemical methods for selective detection of proteins containing PTMs are still lacking. Here, we detail the development of a unique labeling method wherein a synthetic receptor probe for trimethyl lysine (Kme3), CX4-ONBD, is used to direct selective fluorescent labeling of Kme3 histone peptides. This supramolecular approach reverses the paradigm of ligand-directed affinity labeling by making the receptor the synthetic component and the ligand the component to be labeled. We show that the probe mediates a strong turn-on fluorescence response in the presence of a Kme3 histone peptide and shows >5-fold selectivity in covalent labeling over an unmethylated lysine peptide. We also demonstrate the utility of the probe through the design of a turn-on fluorescence assay for histone deacetylase (HDAC) activity and for inhibitor screening and IC50 determination. Our synthetic receptor-mediated affinity labeling approach broadens the scope of PTM detection by chemical means and may facilitate the development of more versatile in vitro enzymatic assays. PMID:27387477

  11. Histone acetyltransferases and histone deacetylases in B- and T-cell development, physiology and malignancy

    PubMed Central

    Haery, Leila; Thompson, Ryan C.; Gilmore, Thomas D.

    2015-01-01

    The development of B and T cells from hematopoietic precursors and the regulation of the functions of these immune cells are complex processes that involve highly regulated signaling pathways and transcriptional control. The signaling pathways and gene expression patterns that give rise to these developmental processes are coordinated, in part, by two opposing classes of broad-based enzymatic regulators: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs and HDACs can modulate gene transcription by altering histone acetylation to modify chromatin structure, and by regulating the activity of non-histone substrates, including an array of immune-cell transcription factors. In addition to their role in normal B and T cells, dysregulation of HAT and HDAC activity is associated with a variety of B- and T-cell malignancies. In this review, we describe the roles of HATs and HDACs in normal B- and T-cell physiology, describe mutations and dysregulation of HATs and HDACs that are implicated lymphoma and leukemia, and discuss HAT and HDAC inhibitors that have been explored as treatment options for leukemias and lymphomas. PMID:26124919

  12. Post-Training Intrahippocampal Inhibition of Class I Histone Deacetylases Enhances Long-Term Object-Location Memory

    ERIC Educational Resources Information Center

    Hawk, Joshua D.; Florian, Cedrick; Abel, Ted

    2011-01-01

    Long-term memory formation involves covalent modification of the histone proteins that package DNA. Reducing histone acetylation by mutating histone acetyltransferases impairs long-term memory, and enhancing histone acetylation by inhibiting histone deacetylases (HDACs) improves long-term memory. Previous studies using HDAC inhibitors to enhance…

  13. Histone Deacetylases in Bone Development and Skeletal Disorders.

    PubMed

    Bradley, Elizabeth W; Carpio, Lomeli R; van Wijnen, Andre J; McGee-Lawrence, Meghan E; Westendorf, Jennifer J

    2015-10-01

    Histone deacetylases (Hdacs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins. Eleven of the 18 Hdacs encoded by the human and mouse genomes depend on Zn(2+) for enzymatic activity, while the other 7, the sirtuins (Sirts), require NAD2(+). Collectively, Hdacs and Sirts regulate numerous cellular and mitochondrial processes including gene transcription, DNA repair, protein stability, cytoskeletal dynamics, and signaling pathways to affect both development and aging. Of clinical relevance, Hdacs inhibitors are United States Food and Drug Administration-approved cancer therapeutics and are candidate therapies for other common diseases including arthritis, diabetes, epilepsy, heart disease, HIV infection, neurodegeneration, and numerous aging-related disorders. Hdacs and Sirts influence skeletal development, maintenance of mineral density and bone strength by affecting intramembranous and endochondral ossification, as well as bone resorption. With few exceptions, inhibition of Hdac or Sirt activity though either loss-of-function mutations or prolonged chemical inhibition has negative and/or toxic effects on skeletal development and bone mineral density. Specifically, Hdac/Sirt suppression causes abnormalities in physiological development such as craniofacial dimorphisms, short stature, and bone fragility that are associated with several human syndromes or diseases. In contrast, activation of Sirts may protect the skeleton from aging and immobilization-related bone loss. This knowledge may prolong healthspan and prevent adverse events caused by epigenetic therapies that are entering the clinical realm at an unprecedented rate. In this review, we summarize the general properties of Hdacs/Sirts and the research that has revealed their essential functions in bone forming cells (e.g., osteoblasts and chondrocytes) and bone resorbing osteoclasts. Finally, we offer predictions on future research in this area and the

  14. Histone Deacetylase 8: Characterization of Physiological Divalent Metal Catalysis.

    PubMed

    Nechay, Michael R; Gallup, Nathan M; Morgenstern, Amanda; Smith, Quentin A; Eberhart, Mark E; Alexandrova, Anastassia N

    2016-07-01

    Histone deacetylases (HDACs) are responsible for the removal of acetyl groups from histones, resulting in gene silencing. Overexpression of HDACs is associated with cancer, and their inhibitors are of particular interest as chemotherapeutics. However, HDACs remain a target of mechanistic debate. HDAC class 8 is the most studied HDAC, and of particular importance due to its human oncological relevance. HDAC8 has traditionally been considered to be a Zn-dependent enzyme. However, recent experimental assays have challenged this assumption and shown that HDAC8 is catalytically active with a variety of different metals, and that it may be a Fe-dependent enzyme in vivo. We studied two opposing mechanisms utilizing a series of divalent metal ions in physiological abundance (Zn(2+), Fe(2+), Co(2+), Mn(2+), Ni(2+), and Mg(2+)). Extensive sampling of the entire protein with different bound metals was done with the mixed quantum-classical QM/DMD method. Density functional theory (DFT) on an unusually large cluster model was used to describe the active site and reaction mechanism. We have found that the reaction profile of HDAC8 is similar among all metals tested, and follows one of the previously published mechanisms, but the rate-determining step is different from the one previously claimed. We further provide a scheme for estimating the metal binding affinities to the protein. We use the quantum theory of atoms in molecules (QTAIM) to understand the different binding affinities for each metal in HDAC8 as well as the ability of each metal to bind and properly orient the substrate for deacetylation. The combination of this data with the catalytic rate constants is required to reproduce the experimentally observed trend in metal-depending performance. We predict Co(2+) and Zn(2+) to be the most active metals in HDAC8, followed by Fe(2+), and Mn(2+) and Mg(2+) to be the least active. PMID:26996235

  15. A novel histone deacetylase inhibitor Chidamide induces apoptosis of human colon cancer cells

    SciTech Connect

    Liu, Lin; Chen, Baoan; Qin, Shukui; Li, Suyi; He, Xiangming; Qiu, Shaomin; Zhao, Wei; Zhao, Hong

    2010-02-05

    Many studies have demonstrated that histone deacetylase (HDAC) inhibitors induce various tumor cells to undergo apoptosis, and such inhibitors have been used in different clinical trials against different human cancers. In this study, we designed and synthesized a novel HDAC inhibitor, Chidamide. We showed that Chidamide was able to increase the acetylation levels of histone H3 and to inhibit the PI3K/Akt and MAPK/Ras signaling pathways, which resulted in arresting colon cancer cells at the G1 phase of the cell cycle and promoting apoptosis. As a result, the proliferation of colon cancer cells was suppressed in vitro. Our data support the potential application of Chidamide as an anticancer agent in treating colon cancer. Future studies are needed to demonstrate its in vivo efficacy.

  16. Feedback Activation of Leukemia Inhibitory Factor Receptor Limits Response to Histone Deacetylase Inhibitors in Breast Cancer.

    PubMed

    Zeng, Hanlin; Qu, Jia; Jin, Nan; Xu, Jun; Lin, Chenchu; Chen, Yi; Yang, Xinying; He, Xiang; Tang, Shuai; Lan, Xiaojing; Yang, Xiaotong; Chen, Ziqi; Huang, Min; Ding, Jian; Geng, Meiyu

    2016-09-12

    Histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits in subtypes of hematological malignancies. However, the efficacy of HDAC inhibitors in solid tumors remains uncertain. This study takes breast cancer as a model to understand mechanisms accounting for limited response of HDAC inhibitors in solid tumors and to seek combination solutions. We discover that feedback activation of leukemia inhibitory factor receptor (LIFR) signaling in breast cancer limits the response to HDAC inhibition. Mechanistically, HDAC inhibition increases histone acetylation at the LIFR gene promoter, which recruits bromodomain protein BRD4, upregulates LIFR expression, and activates JAK1-STAT3 signaling. Importantly, JAK1 or BRD4 inhibition sensitizes breast cancer to HDAC inhibitors, implicating combination inhibition of HDAC with JAK1 or BRD4 as potential therapies for breast cancer. PMID:27622335

  17. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders.

    PubMed

    Kazantsev, Aleksey G; Thompson, Leslie M

    2008-10-01

    Histone deacetylases (HDACs)--enzymes that affect the acetylation status of histones and other important cellular proteins--have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Pharmacological manipulations using small-molecule HDAC inhibitors--which may restore transcriptional balance to neurons, modulate cytoskeletal function, affect immune responses and enhance protein degradation pathways--have been beneficial in various experimental models of brain diseases. Although mounting data predict a therapeutic benefit for HDAC-based therapy, drug discovery and development of clinical candidates face significant challenges. Here, we summarize the current state of development of HDAC therapeutics and their application for the treatment of human brain disorders such as Rubinstein-Taybi syndrome, Rett syndrome, Friedreich's ataxia, Huntington's disease and multiple sclerosis. PMID:18827828

  18. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer

    PubMed Central

    Thurn, K Ted; Thomas, Scott; Moore, Amy; Munster, Pamela N

    2011-01-01

    Histone deacetylases (HDACs) regulate the acetylation of a variety of histone and nonhistone proteins, controlling the transcription and regulation of genes involved in cell cycle control, proliferation, survival, DNA repair and differentiation. Unsurprisingly, HDAC expression is frequently altered in hematologic and solid tumor malignancies. Two HDAC inhibitors (vorinostat and romidepsin) have been approved by the US FDA for the treatment of cutaneous T-cell lymphoma. As single agents, treatment with HDAC inhibitors has demonstrated limited clinical benefit for patients with solid tumors, prompting the investigation of novel treatment combinations with other cancer therapeutics. In this article, the rationales and clinical progress of several combinations with HDAC inhibitors are presented, including DNA-damaging chemotherapeutic agents, radiotherapy, hormonal therapies, DNA methyltransferase inhibitors and various small-molecule inhibitors. The future application of HDAC inhibitors as a treatment for cancer is discussed, examining current hurdles to overcome before realizing the potential of this new approach. PMID:21345145

  19. A Role for Histone Deacetylases in the Cellular and Behavioral Mechanisms Underlying Learning and Memory

    ERIC Educational Resources Information Center

    Mahgoub, Melissa; Monteggia, Lisa M.

    2014-01-01

    Histone deacetylases (HDACs) are a family of chromatin remodeling enzymes that restrict access of transcription factors to the DNA, thereby repressing gene expression. In contrast, histone acetyltransferases (HATs) relax the chromatin structure allowing for an active chromatin state and promoting gene transcription. Accumulating data have…

  20. Effects of Histone Deacetylase Inhibitor Oxamflatin on In Vitro Porcine Somatic Cell Nuclear Transfer Embryos

    PubMed Central

    Hou, Liming; Ma, Fanhua; Yang, Jinzeng; Riaz, Hasan; Wang, Yongliang; Wu, Wangjun; Xia, Xiaoliang; Ma, Zhiyuan; Zhou, Ying; Zhang, Lin; Ying, Wenqin; Xu, Dequan; Zuo, Bo; Ren, Zhuqing

    2014-01-01

    Abstract Low cloning efficiency is considered to be caused by the incomplete or aberrant epigenetic reprogramming of differentiated donor cells in somatic cell nuclear transfer (SCNT) embryos. Oxamflatin, a novel class of histone deacetylase inhibitor (HDACi), has been found to improve the in vitro and full-term developmental potential of SCNT embryos. In the present study, we studied the effects of oxamflatin treatment on in vitro porcine SCNT embryos. Our results indicated that the rate of in vitro blastocyst formation of SCNT embryos treated with 1 μM oxamflatin for 15 h postactivation was significantly higher than all other treatments. Treatment of oxamflatin decreased the relative histone deacetylase (HDAC) activity in cloned embryos and resulted in hyperacetylation levels of histone H3 at lysine 9 (AcH3K9) and histone H4 at lysine 5 (AcH4K5) at pronuclear, two-cell, and four-cell stages partly through downregulating HDAC1. The suppression of HDAC6 through oxamflatin increased the nonhistone acetylation level of α-tubulin during the mitotic cell cycle of early SCNT embryos. In addition, we demonstrated that oxamflatin downregulated DNA methyltransferase 1 (DNMT1) expression and global DNA methylation level (5-methylcytosine) in two-cell-stage porcine SCNT embryos. The pluripotency-related gene POU5F1 was found to be upregulated in the oxamflatin-treated group with a decreased DNA methylation tendency in its promoter regions. Treatment of oxamflatin did not change the locus-specific DNA methylation levels of Sus scrofa heterochromatic satellite DNA sequences at the blastocyst stage. Meanwhile, our findings suggest that treatment with HDACi may contribute to maintaining the stable status of cytoskeleton-associated elements, such as acetylated α-tubulin, which may be the crucial determinants of donor nuclear reprogramming in early SCNT embryos. In summary, oxamflatin treatment improves the developmental potential of porcine SCNT embryos in vitro. PMID

  1. Histone deacetylase inhibitors block IFNγ-induced STAT1 phosphorylation.

    PubMed

    Ginter, Torsten; Bier, Carolin; Knauer, Shirley K; Sughra, Kalsoom; Hildebrand, Dagmar; Münz, Tobias; Liebe, Theresa; Heller, Regine; Henke, Andreas; Stauber, Roland H; Reichardt, Werner; Schmid, Johannes A; Kubatzky, Katharina F; Heinzel, Thorsten; Krämer, Oliver H

    2012-07-01

    Signal transducer and activator of transcription 1 (STAT1) is important for innate and adaptive immunity. Histone deacetylase inhibitors (HDACi) antagonize unbalanced immune functions causing chronic inflammation and cancer. Phosphorylation and acetylation regulate STAT1 and different IFNs induce phosphorylated STAT1 homo-/heterodimers, e.g. IFNα activates several STATs whereas IFNγ only induces phosphorylated STAT1 homodimers. In transformed cells HDACi trigger STAT1 acetylation linked to dephosphorylation by the phosphatase TCP45. It is unclear whether acetylation differentially affects STAT1 activated by IFNα or IFNγ, and if cellular responses to both cytokines depend on a phosphatase-dependent inactivation of acetylated STAT1. Here, we report that HDACi counteract IFN-induced phosphorylation of a critical tyrosine residue in the STAT1 C-terminus in primary cells and hematopoietic cells. STAT1 mutants mimicking a functionally inactive DNA binding domain (DBD) reveal that the number of acetylation-mimicking sites in STAT1 determines whether STAT1 is recruited to response elements after stimulation with IFNγ. Furthermore, we show that IFNα-induced STAT1 heterodimers carrying STAT1 molecules mimicking acetylation bind cognate DNA and provide innate anti-viral immunity. IFNγ-induced acetylated STAT1 homodimers are though inactive, suggesting that heterodimerization and complex formation can rescue STAT1 lacking a functional DBD. Apparently, the type of cytokine determines how acetylation affects the nuclear entry and DNA binding of STAT1. Our data contribute to a better understanding of STAT1 regulation by acetylation. PMID:22425562

  2. Histone deacetylases inhibitors effects on Cryptococcus neoformans major virulence phenotypes

    PubMed Central

    Brandão, Fabiana AS; Derengowski, Lorena S; Albuquerque, Patrícia; Nicola, André M; Silva-Pereira, Ildinete; Poças-Fonseca, Marcio J

    2015-01-01

    Cryptococcus neoformans undergoes phenotypical changes during host infection in order to promote persistence and survival. Studies have demonstrated that such adaptations require alterations in gene transcription networks by distinct mechanisms. Drugs such as the histone deacetylases inhibitors (HDACi) Sodium Butyrate (NaBut) and Trichostatin A (TSA) can alter the chromatin conformation and have been used to modulate epigenetic states in the treatment of diseases such as cancer. In this work, we have studied the effect of NaBut and TSA on the expression of C. neoformans major virulence phenotypes and on the survival rate of an animal model infected with drugs-treated yeasts. Both drugs affected fungal growth at 37°C more intensely than at 30°C; nonetheless, drugs did not affect cell viability at the concentrations we studied. HDACi also provoked the reduction of the fungal capsule expansion. Phospholipases enzyme activity decreased; mating process and melanin synthesis were also affected by both inhibitors. NaBut led to an increase in the population of cells in G2/M. Treated yeast cells, which were washed in order to remove the drugs from the culture medium prior to the inoculation in the Galleria mellonela infection model, did not cause significant difference at the host survival curve when compared to non-treated cells. Overall, NaBut effects on the impairment of C. neoformans main virulence factors were more intense and stable than the TSA effects. PMID:26103530

  3. Regulation of Runx2 by Histone Deacetylases in Bone.

    PubMed

    Vishal, Mohanakrishnan; Ajeetha, Ramachandran; Keerthana, Rajendran; Selvamurugan, Nagarajan

    2016-01-01

    Osteogenesis involves a cascade of processes wherein mesenchymal stem cells differentiate towards osteoblasts, strictly controlled by a number of regulatory factors. Runx2 protein is a key transcription factor which serves as a master regulator for osteogenesis by activating the promoters of various osteoblastic genes. Runx2 is regulated by several cofactors, including the histone deacetylase enzymes known as HDACs. HDACs are a family of proteins that regulate gene expression and/or activity through the mechanism of deacetylation and they can be divided into four classes, namely classes I, II, III and IV HDACs based on their sequence identity and nuclear or cytoplasmic localization. Knockout studies of all classes of HDACs showed their specific developmental roles. Evidence has proved Runx2 to be a repressible target of HDACs and this interplay is found to be a crucial factor controlling osteoblast differentiation. Further, another level of osteogenic regulation involves microRNAs (miRNAs), which are small, non-coding endogenous molecules capable of gene silencing by partial or complete complementary binding of their seed sequences to the 3' untranslated region (UTR) of target mRNAs. In this study, the recent developments on identifying the function of HDACs on Runx2 expression/activity and the impact of miRNAs on HDACs in regulation of osteogenesis are reviewed. PMID:27072566

  4. Histone deacetylase 10 promotes autophagy-mediated cell survival

    PubMed Central

    Oehme, Ina; Linke, Jan-Peter; Böck, Barbara C.; Milde, Till; Lodrini, Marco; Hartenstein, Bettina; Wiegand, Inga; Eckert, Christian; Roth, Wilfried; Kool, Marcel; Kaden, Sylvia; Gröne, Hermann-Josef; Schulte, Johannes H.; Lindner, Sven; Hamacher-Brady, Anne; Brady, Nathan R.; Deubzer, Hedwig E.; Witt, Olaf

    2013-01-01

    Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome. PMID:23801752

  5. Histone deacetylase 10 promotes autophagy-mediated cell survival.

    PubMed

    Oehme, Ina; Linke, Jan-Peter; Böck, Barbara C; Milde, Till; Lodrini, Marco; Hartenstein, Bettina; Wiegand, Inga; Eckert, Christian; Roth, Wilfried; Kool, Marcel; Kaden, Sylvia; Gröne, Hermann-Josef; Schulte, Johannes H; Lindner, Sven; Hamacher-Brady, Anne; Brady, Nathan R; Deubzer, Hedwig E; Witt, Olaf

    2013-07-01

    Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome. PMID:23801752

  6. Hypothalamic leptin action is mediated by histone deacetylase 5.

    PubMed

    Kabra, Dhiraj G; Pfuhlmann, Katrin; García-Cáceres, Cristina; Schriever, Sonja C; Casquero García, Veronica; Kebede, Adam Fiseha; Fuente-Martin, Esther; Trivedi, Chitrang; Heppner, Kristy; Uhlenhaut, N Henriette; Legutko, Beata; Kabra, Uma D; Gao, Yuanqing; Yi, Chun-Xia; Quarta, Carmelo; Clemmensen, Christoffer; Finan, Brian; Müller, Timo D; Meyer, Carola W; Paez-Pereda, Marcelo; Stemmer, Kerstin; Woods, Stephen C; Perez-Tilve, Diego; Schneider, Robert; Olson, Eric N; Tschöp, Matthias H; Pfluger, Paul T

    2016-01-01

    Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment. PMID:26923837

  7. Hypothalamic leptin action is mediated by histone deacetylase 5

    PubMed Central

    Kabra, Dhiraj G.; Pfuhlmann, Katrin; García-Cáceres, Cristina; Schriever, Sonja C.; Casquero García, Veronica; Kebede, Adam Fiseha; Fuente-Martin, Esther; Trivedi, Chitrang; Heppner, Kristy; Uhlenhaut, N. Henriette; Legutko, Beata; Kabra, Uma D.; Gao, Yuanqing; Yi, Chun-Xia; Quarta, Carmelo; Clemmensen, Christoffer; Finan, Brian; Müller, Timo D.; Meyer, Carola W.; Paez-Pereda, Marcelo; Stemmer, Kerstin; Woods, Stephen C.; Perez-Tilve, Diego; Schneider, Robert; Olson, Eric N.; Tschöp, Matthias H.; Pfluger, Paul T.

    2016-01-01

    Hypothalamic leptin signalling has a key role in food intake and energy-balance control and is often impaired in obese individuals. Here we identify histone deacetylase 5 (HDAC5) as a regulator of leptin signalling and organismal energy balance. Global HDAC5 KO mice have increased food intake and greater diet-induced obesity when fed high-fat diet. Pharmacological and genetic inhibition of HDAC5 activity in the mediobasal hypothalamus increases food intake and modulates pathways implicated in leptin signalling. We show HDAC5 directly regulates STAT3 localization and transcriptional activity via reciprocal STAT3 deacetylation at Lys685 and phosphorylation at Tyr705. In vivo, leptin sensitivity is substantially impaired in HDAC5 loss-of-function mice. Hypothalamic HDAC5 overexpression improves leptin action and partially protects against HFD-induced leptin resistance and obesity. Overall, our data suggest that hypothalamic HDAC5 activity is a regulator of leptin signalling that adapts food intake and body weight to our dietary environment. PMID:26923837

  8. Histone deacetylase 3 is necessary for proper brain development.

    PubMed

    Norwood, Jordan; Franklin, Jade M; Sharma, Dharmendra; D'Mello, Santosh R

    2014-12-12

    The functional role of histone deacetylase 3 (HDAC3) in the developing brain has yet to be elucidated. We show that mice lacking HDAC3 in neurons and glia of the central nervous system, Nes-Cre/HDAC3 conditional KO mice, show major abnormalities in the cytoarchitecture of the neocortex and cerebellum and die within 24 h of birth. Later-born neurons do not localize properly in the cortex. A similar mislocalization is observed with cerebellar Purkinje neurons. Although the proportion of astrocytes is higher than normal, the numbers of oligodendrocytes are reduced. In contrast, conditional knockout of HDAC3 in neurons of the forebrain and certain other brain regions, using Thy1-Cre and calcium/calmodulin dependent protein kinase II α-Cre for ablation, produces no overt abnormalities in the organization of cells within the cortex or of cerebellar Purkinje neurons at birth. However, both lines of conditional knockout mice suffer from progressive hind limb paralysis and ataxia and die around 6 weeks after birth. The mice display an increase in overall numbers of cells, higher numbers of astrocytes, and Purkinje neuron degeneration. Taken together, our results demonstrate that HDAC3 plays an essential role in regulating brain development, with effects on both neurons and glia in different brain regions. PMID:25339172

  9. Class IIa Histone Deacetylases Are Conserved Regulators of Circadian Function*

    PubMed Central

    Fogg, Paul C. M.; O'Neill, John S.; Dobrzycki, Tomasz; Calvert, Shaun; Lord, Emma C.; McIntosh, Rebecca L. L.; Elliott, Christopher J. H.; Sweeney, Sean T.; Hastings, Michael H.; Chawla, Sangeeta

    2014-01-01

    Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca2+ and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. PMID:25271152

  10. Regulation of Primitive Hematopoiesis by Class I Histone Deacetylases

    PubMed Central

    Shah, Rishita R.; Koniski, Anne; Shinde, Mansi; Blythe, Shelby A.; Fass, Daniel M.; Haggarty, Stephen J.; Palis, James; Klein, Peter S.

    2013-01-01

    Background Histone deacetylases (HDACs) regulate multiple developmental processes and cellular functions. However, their roles in blood development have not been determined, and in Xenopus laevis, a specific function for HDACs has yet to be identified. Here, we employed the class I selective HDAC inhibitor, valproic acid (VPA), to show that HDAC activity is required for primitive hematopoiesis. Results VPA treatment during gastrulation resulted in a complete absence of red blood cells (RBCs) in Xenopus tadpoles, but did not affect development of other mesodermal tissues, including myeloid and endothelial lineages. These effects of VPA were mimicked by Trichostatin A (TSA), a well-established pan-HDAC inhibitor, but not by valpromide, which is structurally similar to VPA but does not inhibit HDACs. VPA also caused a marked, dose-dependent loss of primitive erythroid progenitors in mouse yolk sac explants at clinically relevant concentrations. In addition, VPA treatment inhibited erythropoietic development downstream of bmp4 and gata1 in Xenopus ectodermal explants. Conclusions These findings suggest an important role for class I HDACs in primitive hematopoiesis. Our work also demonstrates that specific developmental defects associated with exposure to VPA, a significant teratogen in humans, arise through inhibition of class I HDACs. PMID:23184530

  11. Pharmacological Analysis of Vorinostat Analogues as Potential Anti-tumor Agents Targeting Human Histone Deacetylases: an Epigenetic Treatment Stratagem for Cancers.

    PubMed

    Praseetha, Sugathan; Bandaru, Srinivas; Nayarisseri, Anuraj; Sureshkumar, Sivanpillai

    2016-01-01

    Alteration of the acetylation status of chromatin and other non-histone proteins by HDAC inhibitors has evolved as an excellent epigenetic strategy in treatment of cancers. The present study was sought to identify compounds with positive pharmacological profiles targeting HDAC1. Analogues of Vorinostat synthesized by Cai et al, 2015 formed the test compounds for the present pharmacological evaluation. Hydroxamte analogue 6H showed superior pharmacological profile in comparison to all the compounds in the analogue dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify compounds with even better high affinity and pharmacological profile than 6H and Vorinostat, virtual screening was performed. A total of 83 compounds similar to Vorinostat and 154 compounds akin to analogue 6H were retrieved. SCHEMBL15675695 (PubCid: 15739209) and AKOS019005527 (PubCid: 80442147) similar to Vorinostat and 6H, were the best docked compounds among the virtually screened compounds. However, in spite of having good affinity, none of the virtually screened compounds had better affinity than that of 6H. In addition SCHEMBL15675695 was predicted to be a carcinogen while AKOS019005527 is Ames toxic. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report Vorinostat hydroxamate analogue 6H to be a potential candidate for HDAC inhibition in treatment of cancers through an epigenetic strategy. PMID:27039807

  12. Resetting the epigenetic histone code in the MRL-lpr/lpr mouse model of lupus by histone deacetylase inhibition.

    PubMed

    Garcia, Benjamin A; Busby, Scott A; Shabanowitz, Jeffrey; Hunt, Donald F; Mishra, Nilamadhab

    2005-01-01

    The baseline level of gene expression varies between healthy controls and systemic lupus erythematosus (SLE) patients, and among SLE patients themselves. These variations may explain the different clinical manifestations and severity of disease observed in SLE. Epigenetic mechanisms, which involve DNA and histone modifications, are predictably associated with distinct transcriptional states. To understand the interplay between various histone modifications, including acetylation and methylation, and lupus disease, we performed differential expression histone modification analysis in splenocytes from the MRL-lpr/lpr mouse model of lupus. Using stable isotope labeling in combination with mass spectrometry, we found global site-specific hypermethylation (except H3 K4 methylation) and hypoacetylation in histone H3 and H4 MRL-lpr/lpr mice compared to control MRL/MPJ mice. Moreover, we have identified novel histone modifications such as H3 K18 methylation, H4 K31 methylation, and H4 K31 acetylation that are differentially expressed in MRL-lpr/lpr mice compared to controls. Finally, in vivo administration of the histone deacetylase inhibitor trichostatin A (TSA) corrected the site-specific hypoacetylation states on H3 and H4 in MRL-lpr/lpr mice with improvement of disease phenotype. Thus, this study is the first to establish the association between aberrant histone codes and pathogenesis of autoimmune disease SLE. These aberrant post-translational histone modifications can therefore be reset with histone deacetylase inhibition in vivo. PMID:16335948

  13. Histone deacetylase inhibitor sulforaphane: The phytochemical with vibrant activity against prostate cancer.

    PubMed

    Ganai, Shabir Ahmad

    2016-07-01

    Epigenetic modifications are closely involved in the patho-physiology of prostate cancer. Histone deacetylases (HDACs), the transcriptional corepressors have strong crosstalk with prostate cancer progression as they influence various genes related to tumour suppression. HDACs play a marked role in myriad of human cancers and as such are emerging as striking molecular targets for anticancer drugs and therapy. Histone deacetylase inhibitors (HDACi), the small-molecules interfering HDACs are emerging as promising chemotherapeutic agents. These inhibitors have shown multiple effects including cell growth arrest, differentiation and apoptosis in prostate cancer. The limited efficacy of HDACi as single agents in anticancer therapy has been strongly improved via novel therapeutic strategies like doublet therapy (combined therapy). More than 20HDACi have already entered into the journey of clinical trials and four have been approved by FDA against diverse cancers. This review deals with plant derived HDACi sulphoraphane (SFN; 1-isothiocyanato-4-(methylsulfinyl)-butane) and its potential role in prostate cancer therapy along with the underlying molecular mechanism being involved. The article further highlights the therapeutic strategy that can be utilized for sensitizing conventional therapy resistant cases and for acquiring the maximum therapeutic benefit from this promising inhibitor in the upcoming future. PMID:27261601

  14. The transposon-driven evolutionary origin and basis of histone deacetylase functions and limitations in disease prevention.

    PubMed

    Peek, Gregory W; Tollefsbol, Trygve O

    2011-08-01

    Histone deacetylases (HDACs) are homologous to prokaryotic enzymes that removed acetyl groups from non-histone proteins before the evolution of eukaryotic histones. Enzymes inherited from prokaryotes or from a common ancestor were adapted for histone deacetylation, while useful deacetylation of non-histone proteins was selectively retained. Histone deacetylation served to prevent transcriptions with pathological consequences, including the expression of viral DNA and the deletion or dysregulation of vital genes by random transposon insertions. Viruses are believed to have evolved from transposons, with transposons providing the earliest impetus of HDAC evolution. Because of the wide range of genes potentially affected by transposon insertions, the range of diseases that can be prevented by HDACs is vast and inclusive. Repressive chromatin modifications that may prevent transcription also include methylation of selective lysine residues of histones H3 and H4 and the methylation of selective DNA cytosines following specific histone lysine methylation. Methylation and acetylation of individual histone residues are mutually exclusive. While transposons were sources of disease to be prevented by HDAC evolution, they were also the source of numerous and valuable coding and regulatory sequences recruited by "molecular domestication." Those sequences contribute to evolved complex transcription regulation in which components with contradictory effects, such as HDACs and HATs, may be coordinated and complementary. Within complex transcription regulation, however, HDACs remain ineffective as defense against some critical infectious and non-infectious diseases because evolutionary compromises have rendered their activity transient. PMID:22704332

  15. Activation and Inhibition of Histone Deacetylase 8 by Monovalent Cations*

    PubMed Central

    Gantt, Stephanie L.; Joseph, Caleb G.; Fierke, Carol A.

    2010-01-01

    The metal-dependent histone deacetylases (HDACs) catalyze hydrolysis of acetyl groups from acetyllysine side chains and are targets of cancer therapeutics. Two bound monovalent cations (MVCs) of unknown function have been previously observed in crystal structures of HDAC8; site 1 is near the active site, whereas site 2 is located >20 Å from the catalytic metal ion. Here we demonstrate that one bound MVC activates catalytic activity (K1/2 = 3.4 mm for K+), whereas the second, weaker-binding MVC (K1/2 = 26 mm for K+) decreases catalytic activity by 11-fold. The weaker binding MVC also enhances the affinity of the HDAC inhibitor suberoylanilide hydroxamic acid by 5-fold. The site 1 MVC is coordinated by the side chain of Asp-176 that also forms a hydrogen bond with His-142, one of two histidines important for catalytic activity. The D176A and H142A mutants each increase the K1/2 for potassium inhibition by ≥40-fold, demonstrating that the inhibitory cation binds to site 1. Furthermore, the MVC inhibition is mediated by His-142, suggesting that this residue is protonated for maximal HDAC8 activity. Therefore, His-142 functions either as an electrostatic catalyst or a general acid. The activating MVC binds in the distal site and causes a time-dependent increase in activity, suggesting that the site 2 MVC stabilizes an active conformation of the enzyme. Sodium binds more weakly to both sites and activates HDAC8 to a lesser extent than potassium. Therefore, it is likely that potassium is the predominant MVC bound to HDAC8 in vivo. PMID:20029090

  16. Histone deacetylases (HDACs) in XPC gene silencing and bladder cancer

    PubMed Central

    2011-01-01

    Bladder cancer is one of the most common malignancies and causes hundreds of thousands of deaths worldwide each year. Bladder cancer is strongly associated with exposure to environmental carcinogens. It is believed that DNA damage generated by environmental carcinogens and their metabolites causes development of bladder cancer. Nucleotide excision repair (NER) is the major DNA repair pathway for repairing bulk DNA damage generated by most environmental carcinogens, and XPC is a DNA damage recognition protein required for initiation of the NER process. Recent studies demonstrate reduced levels of XPC protein in tumors for a majority of bladder cancer patients. In this work we investigated the role of histone deacetylases (HDACs) in XPC gene silencing and bladder cancer development. The results of our HDAC inhibition study revealed that the treatment of HTB4 and HTB9 bladder cancer cells with the HDAC inhibitor valproic acid (VPA) caused an increase in transcription of the XPC gene in these cells. The results of our chromatin immunoprecipitation (ChIP) studies indicated that the VPA treatment caused increased binding of both CREB1 and Sp1 transcription factors at the promoter region of the XPC gene for both HTB4 and HTB9 cells. The results of our immunohistochemistry (IHC) staining studies further revealed a strong correlation between the over-expression of HDAC4 and increased bladder cancer occurrence (p < 0.001) as well as a marginal significance of increasing incidence of HDAC4 positivity seen with an increase in severity of bladder cancer (p = 0.08). In addition, the results of our caspase 3 activation studies demonstrated that prior treatment with VPA increased the anticancer drug cisplatin-induced activation of caspase 3 in both HTB4 and HTB9 cells. All of these results suggest that the HDACs negatively regulate transcription of the XPC gene in bladder cancer cells and contribute to the severity of bladder tumors. PMID:21507255

  17. Histone Deacetylases Inhibitors in the Treatment of Retinal Degenerative Diseases: Overview and Perspectives

    PubMed Central

    Dai, Xufeng; Du, Wei; Pang, Ji-jing

    2015-01-01

    Retinal degenerative diseases are one of the important refractory ophthalmic diseases, featured with apoptosis of photoreceptor cells. Histone acetylation and deacetylation can regulate chromosome assembly, gene transcription, and posttranslational modification, which are regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. The histone deacetylase inhibitors (HDACis) have the ability to cause hyperacetylation of histone and nonhistone proteins, resulting in a variety of effects on cell proliferation, differentiation, anti-inflammation, and anti-apoptosis. Several HDACis have been approved for clinical trials to treat cancer. Studies have shown that HDACis have neuroprotective effects in nervous system damage. In this paper, we will summarize the neuroprotective effects of common HDACis in retinal degenerative diseases and make a prospect to the applications of HDACis in the treatment of retinal degenerative diseases in the future. PMID:26137316

  18. Extensive and varied modifications in histone H2B of wildtype and histone deacetylase 1-mutant Neurospora crassa

    PubMed Central

    Anderson, D.C.; Green, George R.; Smith, Kristina; Selker, Eric U.

    2010-01-01

    DNA methylation is deficient in a histone deacetylase 1 (HDA11) mutant (hda-1) strain of Neurospora crassa with inactivated histone deacetylase 1. Difference 2D gels identified the primary histone deacetylase 1 target as histone H2B. Acetylation was identified by LC/MS/MS at 5 different lysines in wild type H2B, and at 11 lysines in hda-1 H2B, suggesting Neurospora H2B is a complex combination of different acetylated species. Individual 2D gel spots were shifted by single lysine acetylations. FTICR MS-observed methylation ladders identify an ensemble of 20–25 or more modified forms for each 2D gel spot. Twelve different lysines or arginines were methylated in H2B from wild type or hda-1; only two were in the N-terminal tail. Arginines were modified by monomethylation, dimethylation or deimination. H2B from wild type and hda-1 ensembles may thus differ by acetylation at multiple sites, and by additional modifications. Combined with asymmetry-generated diversity in H2B structural states in nucleosome core particles, the extensive modifications identified here can create substantial histone-generated structural diversity in nucleosome core particles. PMID:20462202

  19. Histone deacetylase inhibitors: a review on class-I specific inhibition.

    PubMed

    Behera, Jagannath; Jayprakash, Venkatesan; Sinha, Barij Nayan

    2015-01-01

    Histone Deacetylase (HDAC) is an established and validated target for the treatment of cancer. It has been attempted to present a comprehensive review on the inhibitors for Class-I Histone Deacetylase enzyme family, reported during the period from 2002 to 2012. This review has summarized the inhibitors, based on their specificity towards different isoforms within this class. Further various recent United State (US) patents and the HDAC inhibitors, used singly or in combination undergoing clinical trial as anticancer agents have been reviewed. Three such inhibitors SAHA, Romidepsin and Belinostat have already been approved by the US-FDA for the treatment of cancer. PMID:25994050

  20. Post-translational Modifications Regulate Class IIa Histone Deacetylase (HDAC) Function in Health and Disease*

    PubMed Central

    Mathias, Rommel A.; Guise, Amanda J.; Cristea, Ileana M.

    2015-01-01

    Class IIa histone deacetylases (HDACs4, -5, -7, and -9) modulate the physiology of the human cardiovascular, musculoskeletal, nervous, and immune systems. The regulatory capacity of this family of enzymes stems from their ability to shuttle between nuclear and cytoplasmic compartments in response to signal-driven post-translational modification. Here, we review the current knowledge of modifications that control spatial and temporal histone deacetylase functions by regulating subcellular localization, transcriptional functions, and cell cycle-dependent activity, ultimately impacting on human disease. We discuss the contribution of these modifications to cardiac and vascular hypertrophy, myoblast differentiation, neuronal cell survival, and neurodegenerative disorders. PMID:25616866

  1. Histone deacetylase inhibition regulates miR-449a levels in skeletal muscle cells.

    PubMed

    Poddar, Shagun; Kesharwani, Devesh; Datta, Malabika

    2016-08-01

    microRNAs (miRNAs) are small non-coding RNAs that regulate cellular processes by fine-tuning the levels of their target mRNAs. However, the regulatory elements determining cellular miRNA levels are not well studied. Previously, we had described an altered miRNA signature in the skeletal muscle of db/db mice. Here, we sought to explore the role of epigenetic mechanisms in altering these miRNAs. We show that histone deacetylase (HDAC) protein levels and activity are upregulated in the skeletal muscle of diabetic mice. In C2C12 cells, HDAC inhibition using suberoylanilide hydroxamic acid (SAHA) altered the levels of 24 miRNAs: 15 were downregulated and 9 were upregulated. miR-449a, an intronic miRNA localized within the Cdc20b gene, while being downregulated in the skeletal muscle of diabetic mice, was the most highly upregulated during HDAC inhibition. The host gene, Cdc20b, was also significantly upregulated during HDAC inhibition. Bioinformatics analyses identified a common promoter for both Cdc20b and miR-449a that harbors significant histone acetylation marks, suggesting the possibility of regulation by histone acetylation-deacetylation. These observations suggest an inverse correlation between miR-449a levels and HDAC activity, in both SAHA-treated skeletal muscle cells and db/db mice skeletal muscle. Further, in SAHA-treated C2C12 cells, we observed augmented occupancy of acetylated histones on the Cdc20b/miR-449a promoter, which possibly promotes their upregulation. In vivo injection of SAHA to db/db mice significantly restored skeletal muscle miR-449a levels. Our results provide insights into the potential regulatory role of epigenetic histone acetylation of the miR-449a promoter that may regulate its expression in the diabetic skeletal muscle. PMID:27184529

  2. Inhibition of Histone Deacetylases Enhances the Osteogenic Differentiation of Human Periodontal Ligament Cells.

    PubMed

    Huynh, Nam Cong-Nhat; Everts, Vincent; Pavasant, Prasit; Ampornaramveth, Ruchanee Salingcarnboriboon

    2016-06-01

    One of the characteristics of periodontal ligament (PDL) cells is their plasticity. Yet, the underlying mechanisms responsible for this phenomenon are unknown. One possible mechanism might be related to epigenetics, since histone deacetylases (HDACs) have been shown to play a role in osteoblast differentiation. This study was aimed to investigate the role of HDACs in osteogenic differentiation of human PDL (hPDL) cells. HDAC inhibitor trichostatin A (TSA) had no effect on cell viability as was assessed by MTT assay. Osteogenic and adipogenic differentiation was analyzed by gene expression, ALP activity and mineral deposition. Western blotting was used to investigate the effect of TSA on histone acetylation and protein expression. In the presence of the HDAC inhibitor osteogenic differentiation was induced; osteoblast-related gene expression was increased significantly. ALP activity and mineral nodule formation were also enhanced. Inhibition of HDACs did not induce differentiation into the adipocyte lineage. hPDL highly expressed HDACs of both class I (HDAC 1, 2, 3) and class II (HDAC 4, 6). During osteogenic differentiation HDAC 3 expression gradually decreased. This was apparent in the absence and presence of the inhibitor. The level of acetylated Histone H3 was increased during osteogenic differentiation. Inhibition of HDAC activity induced hyperacetylation of Histone H3, therefore, demonstrating Histone H3 as a candidate target molecule for HDAC inhibition. In conclusion, hPDL cells express a distinguished series of HDACs and these enzymes appear to be involved in osteogenic differentiation. This finding suggests a potential application of TSA for bone regeneration therapy by hPDL cells. PMID:27043246

  3. In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs

    PubMed Central

    2015-01-01

    Epigenetic enzymes are now targeted to treat the underlying gene expression dysregulation that contribute to disease pathogenesis. Histone deacetylases (HDACs) have shown broad potential in treatments against cancer and emerging data supports their targeting in the context of cardiovascular disease and central nervous system dysfunction. Development of a molecular agent for non-invasive imaging to elucidate the distribution and functional roles of HDACs in humans will accelerate medical research and drug discovery in this domain. Herein, we describe the synthesis and validation of an HDAC imaging agent, [11C]6. Our imaging results demonstrate that this probe has high specificity, good selectivity, and appropriate kinetics and distribution for imaging HDACs in the brain, heart, kidney, pancreas, and spleen. Our findings support the translational potential for [11C]6 for human epigenetic imaging. PMID:25203558

  4. Novel Inhibitor of Plasmodium Histone Deacetylase That Cures P. berghei-Infected Mice▿

    PubMed Central

    Agbor-Enoh, S.; Seudieu, C.; Davidson, E.; Dritschilo, A.; Jung, M.

    2009-01-01

    Histone deacetylases (HDAC) are potential targets for the development of new antimalarial drugs. The growth of Plasmodium falciparum and other apicomplexans can be suppressed in the presence of potent HDAC inhibitors in vitro and in vivo; however, in vivo parasite suppression is generally incomplete or reversible after the discontinuation of drug treatment. Furthermore, most established HDAC inhibitors concurrently show broad toxicities against parasites and human cells and high drug concentrations are required for effective antimalarial activity. Here, we report on HDAC inhibitors that are potent against P. falciparum at subnanomolar concentrations and that have high selectivities; the lead compounds have mean 50% inhibitory concentrations for the killing of the malaria parasite up to 950 times lower than those for the killing of mammalian cells. These potential drugs improved survival and completely and irreversibly suppressed parasitemia in P. berghei-infected mice. PMID:19223622

  5. [Histone deacetylases: a new class of efficient anti-tumor drugs].

    PubMed

    Mottet, Denis; Castronovo, Vincent

    2008-01-01

    Circa twenty-five years ago, cancer research was dominated by the concept that the origin of cancer was genetic. Thousands of genetic alterations have indeed been identified involving more than hundred different genes in cancer development. Today, the model has evolved: it has been demonstrated that malignancies can be initiated not only through genetic alterations but also through epigenetic deregulations. By altering the expression of gene involved in cell regulation, epigenetic alterations, such as histone acetylation, play a key role in the initiation and progression of neoplasm. It has been shown that an imbalance between the acelylated and deacetylated status of chromatin is significantly involved in the acquisition of a malignant phenotype. Thus, the modulation of the histone acetylation level by histone deacetylase (HDAC) inhibitors could lead to a genetic re-programmation in cancer cells that would favor apoptosis and prevent proliferation. The potential therapeutic value of several HDAC inhibitors for cancer patients has been evaluated in clinical assays with very promising outcome. Indeed, the first inhibitors available for patients has been recently approved for cancer patients tracing the way for a new class of promising anti-cancer therapy modalities. PMID:18789222

  6. Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome

    PubMed Central

    Bjornsson, Hans T.; Benjamin, Joel S.; Zhang, Li; Weissman, Jacqueline; Gerber, Elizabeth E.; Chen, Yi-Chun; Vaurio, Rebecca G.; Potter, Michelle C.; Hansen, Kasper D.; Dietz, Harry C.

    2015-01-01

    Kabuki syndrome is caused by haploinsufficiency for either of two genes that promote the opening of chromatin. If an imbalance between open and closed chromatin is central to the pathogenesis of Kabuki syndrome, agents that promote chromatin opening might have therapeutic potential. We have characterized a mouse model of Kabuki syndrome with a heterozygous deletion in the gene encoding the lysine-specific methyltransferase 2D (Kmt2d), leading to impairment of methyltransferase function. In vitro reporter alleles demonstrated a reduction in histone 4 acetylation and histone 3 lysine 4 trimethylation (H3K4me3) activity in mouse embryonic fibroblasts from Kmt2d+/βGeo mice. These activities were normalized in response to AR-42, a histone deacetylase inhibitor. In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d+/βGeo mice correlated with reduced neurogenesis and hippocampal memory defects. These abnormalities improved upon postnatal treatment with AR-42. Our work suggests that a reversible deficiency in postnatal neurogenesis underlies intellectual disability in Kabuki syndrome. PMID:25273096

  7. Expression and functional analysis of the plant-specific histone deacetylase HDT701 in rice

    PubMed Central

    Zhao, Jinhui; Zhang, Jianxia; Zhang, Wei; Wu, Kunlin; Zheng, Feng; Tian, Lining; Liu, Xuncheng; Duan, Jun

    2015-01-01

    Reversible histone acetylation and deacetylation at the N-terminus of histone tails play a crucial role in regulating eukaryotic gene activity. Acetylation of core histones is associated with gene activation, whereas deacetylation of histone is often correlated with gene repression. The level of histone acetylation is antagonistically catalyzed by histone acetyltransferases citation(HATs) and histone deacetylases (HDACs). In this work, we examined the subcellular localization, expression pattern and function of HDT701, a member of the plant-specific HD2-type histone deacetylase in rice. HDT701 is localized at the subcellular level in the nucleus. Histochemical GUS-staining analysis revealed that HDT701 is constitutively expressed throughout the life cycle of rice. Overexpression of HDT701 in rice decreases ABA, salt and osmotic stress resistance during seed germination. Delayed seed germination of HDT701 overexpression lines is associated with decreased histone H4 acetylation and down-regulated expression of GA biosynthetic genes. Moreover, overexpression of HDT701 in rice enhances salt and osmotic stress resistance during the seedling stage. Taken together, our findings suggested that HDT701 may play an important role in regulating seed germination in response to abiotic stresses in rice. PMID:25653654

  8. Histone Deacetylase Inhibitors: The Epigenetic Therapeutics That Repress Hypoxia-Inducible Factors

    PubMed Central

    Chen, Shuyang; Sang, Nianli

    2011-01-01

    Histone deacetylase inhibitors (HDACIs) have been actively explored as a new generation of chemotherapeutics for cancers, generally known as epigenetic therapeutics. Recent findings indicate that several types of HDACIs repress angiogenesis, a process essential for tumor metabolism and progression. Accumulating evidence supports that this repression is mediated by disrupting the function of hypoxia-inducible factors (HIF-1, HIF-2, and collectively, HIF), which are the master regulators of angiogenesis and cellular adaptation to hypoxia. Since HIF also regulate glucose metabolism, cell survival, microenvironment remodeling, and other alterations commonly required for tumor progression, they are considered as novel targets for cancer chemotherapy. Though the precise biochemical mechanism underlying the HDACI-triggered repression of HIF function remains unclear, potential cellular factors that may link the inhibition of deacetylase activity to the repression of HIF function have been proposed. Here we review published data that inhibitors of type I/II HDACs repress HIF function by either reducing functional HIF-1α levels, or repressing HIF-α transactivation activity. In addition, underlying mechanisms and potential proteins involved in the repression will be discussed. A thorough understanding of HDACI-induced repression of HIF function may facilitate the development of future therapies to either repress or promote angiogenesis for cancer or chronic ischemic disorders, respectively. PMID:21151670

  9. Zyflamend, a polyherbal mixture, down regulates class I and class II histone deacetylases and increases p21 levels in castrate-resistant prostate cancer cells

    PubMed Central

    2014-01-01

    Background Zyflamend, a mixture containing extracts of ten herbs, has shown promise in a variety of preclinical cancer models, including prostate cancer. The current experiments were designed to investigate the effects of Zyflamend on the expression of class I and II histone deacetylases, a family of enzymes known to be over expressed in a variety of cancers. Methods CWR22Rv1 cells, a castrate-resistant prostate cancer cell line, were treated with Zyflamend and the expression of class I and II histone deacetylases, along with their downstream target the tumor suppressor gene p21, was investigated. Involvement of p21 was confirmed with siRNA knockdown and over expression experiments. Results Zyflamend down-regulated the expression of all class I and II histone deacetylases where Chinese goldthread and baikal skullcap (two of its components) appear to be primarily responsible for these results. In addition, Zyflamend up regulated the histone acetyl transferase complex CBP/p300, potentially contributing to the increase in histone 3 acetylation. Expression of the tumor suppressor gene p21, a known downstream target of histone deacetylases and CBP/p300, was increased by Zyflamend treatment and the effect on p21 was, in part, mediated through Erk1/2. Knockdown of p21 with siRNA technology attenuated Zyflamend-induced growth inhibition. Over expression of p21 inhibited cell growth and concomitant treatment with Zyflamend enhanced this effect. Conclusions Our results suggest that the extracts of this polyherbal combination increase histone 3 acetylation, inhibit the expression of class I and class II histone deacetylases, increase the activation of CBP/p300 and inhibit cell proliferation, in part, by up regulating p21 expression. PMID:24555771

  10. Histone/protein deacetylase SIRT1 is an anticancer therapeutic target

    PubMed Central

    Hwang, Bor-Jang; Madabushi, Amrita; Jin, Jin; Lin, Shiou-Yuh S; Lu, A-Lien

    2014-01-01

    SIRT1, a member of the NAD+-dependent histone/protein deacetylase family, is involved in chromatin remodeling, DNA repair, and stress response and is a potential drug target. 5-fluorouracil (FU) and the SN1-type DNA methylating agent temozolomide (TMZ) are anticancer agents. In this study, we demonstrate that sirt1 knockout mouse embryonic fibroblast cells are more sensitive to FU and DNA methylating agents than normal cells. Based on these findings, the chemotherapy efficacy of SIRT1 inhibitors in combination with FU or TMZ were tested with human breast cancer cells. We found that treatments combining SIRT1 inhibitors with FU or TMZ show synergistic reduction of cell viability and colony formation of breast cancer cells. Thus, inhibition of SIRT1 activity provides a novel anticancer strategy. PMID:24959376

  11. Single-Molecule Electronic Measurements of the Dynamic Flexibility of Histone Deacetylases

    NASA Astrophysics Data System (ADS)

    Froberg, James; You, Seungyong; Yu, Junru; Haldar, Manas; Sedigh, Abbas; Mallik, Sanku; Srivastava, D. K.; Choi, Yongki

    Due to their involvement in epigenetic regulation, histone deacetylases (HDACs) have gained considerable interest in designing drugs for treatment of a variety of human diseases including cancers. Recently, we applied a label-free, electronic single-molecule nano-circuit technique to gain insight into the contribution of the dynamic flexibility in HDACs structure during the course of substrates/ ligands binding and catalysis. We observed that HDAC8 has two major (dynamically interconvertible) conformational states, ``ground (catalytically unfavorable)'' and ``transition (catalytically favorable)''. In addition, we found that its cognate substrates/ligands reciprocally catalyze the transition of the ground to the transition state conformation of HDAC8. Thus, we propose that both enzymes and their substrates/ligands serve as ``catalysts'' in facilitating the structural changes of each other and promoting the overall chemical transformation reaction. Such new information provides the potential for designing a new class of mechanism-based inhibitors and activators of HDAC8 for treating human diseases.

  12. Nanoparticle formulations of histone deacetylase inhibitors for effective chemoradiotherapy in solid tumors

    PubMed Central

    Wang, Edina C.; Min, Yuanzeng; Palm, Robert C.; Fiordalisi, James J.; Wagner, Kyle T.; Hyder, Nabeel; Cox, Adrienne D.; Caster, Joseph; Tian, Xi; Wang, Andrew Z.

    2015-01-01

    Histone deacetylase inhibitors (HDACIs) represent a class of promising agents that can improve radiotherapy in cancer treatment. However, the full therapeutic potential of HDACIs as radiosensitizers has been restricted by limited efficacy in solid malignancies. In this study, we report the development of nanoparticle (NP) formulations of HDACIs that overcome these limitations, illustrating their utility to improve the therapeutic ratio of the clinically established first generation HDACI vorinostat and a novel second generation HDACI quisinostat. We demonstrate that NP HDACIs are potent radiosensitizers in vitro and are more effective as radiosensitizers than small molecule HDACIs in vivo using mouse xenograft models of colorectal and prostate carcinomas. We found that NP HDACIs enhance the response of tumor cells to radiation through the prolongation of γ-H2AX foci. Our work illustrates an effective method for improving cancer radiotherapy treatment. PMID:25771011

  13. Optimization of a series of potent and selective ketone histone deacetylase inhibitors.

    PubMed

    Pescatore, Giovanna; Kinzel, Olaf; Attenni, Barbara; Cecchetti, Ottavia; Fiore, Fabrizio; Fonsi, Massimiliano; Rowley, Michael; Schultz-Fademrecht, Carsten; Serafini, Sergio; Steinkühler, Christian; Jones, Philip

    2008-10-15

    Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in the clinic. Herein we describe the optimization of a series of ketone small molecule HDAC inhibitors leading to potent and selective class I HDAC inhibitors with good dog PK. PMID:18809328

  14. The Cohesin loading factor NIPBL recruits histone deacetylases to mediate local chromatin modifications

    PubMed Central

    Jahnke, Philipp; Xu, Weizhen; Wülling, Manuela; Albrecht, Melanie; Gabriel, Heinz; Gillessen-Kaesbach, Gabriele; Kaiser, Frank J.

    2008-01-01

    Cornelia de Lange Syndrome (CdLS) is a rare congenital malformation disorder. About half of the patients with CdLS carry mutations in the NIPBL gene encoding the NIPBL protein, a subunit of the Cohesin loading complex. Recent studies show association of Cohesin with chromatin-remodeling complexes, either by establishing cohesion or by recruiting Cohesin to specific chromosome locations. In yeast two-hybrid assays, we identified an interaction of NIPBL with the histone deacetylases -1 and -3. These interactions were confirmed in mammalian cells by coimmunoprecipitation and a critical region for interaction was defined to a stretch of 163 amino acids of a highly conserved region of NIPBL, which is mutated in patients with CdLS. Utilizing reporter gene assays, we could show that NIPBL fused to the GAL4-DNA-binding domain (GAL4-DBD) represses promoter activity via the recruitment of histone deacetylases. Interestingly, this effect is dramatically reduced by both NIPBL missense mutations identified in CdLS and by chemical inhibition of the histone deacetylases. Our data are the first to indicate a molecular and functional connection of NIPBL with chromatin-remodeling processes via the direct interaction with histone deacetylases. PMID:18854353

  15. Graphene oxide-peptide nanoassembly as a general approach for monitoring the activity of histone deacetylases.

    PubMed

    Liang, Ping; Li, Qing; Wu, Zhan; Jiang, Jian-Hui; Yu, Ru-Qin

    2016-06-20

    A novel fluorescent sensor using graphene oxide (GO)-peptide nanoassembly is developed for histone deacetylases (HDACs) based on deacetylation mediated cleavage of substrate peptides, which provides a simple, cost-effective platform for monitoring the activity of HDACs. PMID:27194207

  16. Histone deacetylase activity and recurrent bacterial bronchitis in severe eosinophilic asthma.

    PubMed

    Zuccaro, L; Cox, A; Pray, C; Radford, K; Novakowski, K; Dorrington, M; Surette, M G; Bowdish, D; Nair, P

    2016-04-01

    An increase in P13 Kinase activity and an associated reduction in histone deacetylase activity may contribute to both relative steroid insensitivity in patients with severe eosinophilic asthma and impaired macrophage scavenger function and susceptibility to recurrent infective bronchitis that may, in turn, contribute to further steroid insensitivity. PMID:26715426

  17. Droxinostat, a Histone Deacetylase Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cell Lines via Activation of the Mitochondrial Pathway and Downregulation of FLIP1

    PubMed Central

    Liu, Jing; Li, Guangming; Wang, Xiang; Wang, Liang; Zhao, Rui; Wang, Juanxia; Kong, Yin; Ding, Jie; Li, Juan; Zhang, Lingyi

    2016-01-01

    Background: The current chemotherapeutic outcomes for hepatocellular carcinoma (HCC) are not encouraging, and long-term survival of this patient group remains poor. Recent studies have demonstrated the utility of histone deacetylase inhibitors that can disrupt cell proliferation and survival in HCC management. However, the effects of droxinostat, a type of histone deacetylase inhibitor, on HCC remain to be established. Methods: The effects of droxinostat on HCC cell lines SMMC-7721 and HepG2 were investigated. Histone acetylation and apoptosis-modulating proteins were assessed via Western blot. Proliferation was examined with 3-(4, 5 dimetyl-2-thiazolyl)-2, 5-diphenyl 2H-tetrazolium bromide, cell proliferation, and real-time cell viability assays, and apoptosis with flow cytometry. Results: Droxinostat inhibited proliferation and colony formation of the HCC cell lines examined. Hepatoma cell death was induced through activation of the mitochondrial apoptotic pathway and downregulation of FLIP expression. Droxinostat suppressed histone deacetylase (HDAC) 3 expression and promoted acetylation of histones H3 and H4. Knockdown of HDAC3 induced hepatoma cell apoptosis and histone H3 and H4 acetylation. Conclusions: Droxinostat suppresses HDAC3 expression and induces histone acetylation and HCC cell death through activation of the mitochondrial apoptotic pathway and downregulation of FLIP, supporting its potential application in the treatment of HCC. PMID:26947884

  18. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation

    PubMed Central

    Zhang, Yi; Ng, Huck-Hui; Erdjument-Bromage, Hediye; Tempst, Paul; Bird, Adrian; Reinberg, Danny

    1999-01-01

    ATP-dependent nucleosome remodeling and core histone acetylation and deacetylation represent mechanisms to alter nucleosome structure. NuRD is a multisubunit complex containing nucleosome remodeling and histone deacetylase activities. The histone deacetylases HDAC1 and HDAC2 and the histone binding proteins RbAp48 and RbAp46 form a core complex shared between NuRD and Sin3-histone deacetylase complexes. The histone deacetylase activity of the core complex is severely compromised. A novel polypeptide highly related to the metastasis-associated protein 1, MTA2, and the methyl-CpG-binding domain-containing protein, MBD3, were found to be subunits of the NuRD complex. MTA2 modulates the enzymatic activity of the histone deacetylase core complex. MBD3 mediates the association of MTA2 with the core histone deacetylase complex. MBD3 does not directly bind methylated DNA but is highly related to MBD2, a polypeptide that binds to methylated DNA and has been reported to possess demethylase activity. MBD2 interacts with the NuRD complex and directs the complex to methylated DNA. NuRD may provide a means of gene silencing by DNA methylation. PMID:10444591

  19. Ky-2, a Histone Deacetylase Inhibitor, Enhances High-Salinity Stress Tolerance in Arabidopsis thaliana.

    PubMed

    Sako, Kaori; Kim, Jong-Myong; Matsui, Akihiro; Nakamura, Kotaro; Tanaka, Maho; Kobayashi, Makoto; Saito, Kazuki; Nishino, Norikazu; Kusano, Miyako; Taji, Teruaki; Yoshida, Minoru; Seki, Motoaki

    2016-04-01

    Adaptation to environmental stress requires genome-wide changes in gene expression. Histone modifications are involved in gene regulation, but the role of histone modifications under environmental stress is not well understood. To reveal the relationship between histone modification and environmental stress, we assessed the effects of inhibitors of histone modification enzymes during salinity stress. Treatment with Ky-2, a histone deacetylase inhibitor, enhanced high-salinity stress tolerance in Arabidopsis. We confirmed that Ky-2 possessed inhibition activity towards histone deacetylases by immunoblot analysis. To investigate how Ky-2 improved salt stress tolerance, we performed transcriptome and metabolome analysis. These data showed that the expression of salt-responsive genes and salt stress-related metabolites were increased by Ky-2 treatment under salinity stress. A mutant deficient inAtSOS1(Arabidopis thaliana SALT OVERLY SENSITIVE 1), which encodes an Na(+)/H(+)antiporter and was among the up-regulated genes, lost the salinity stress tolerance conferred by Ky-2. We confirmed that acetylation of histone H4 atAtSOS1was increased by Ky-2 treatment. Moreover, Ky-2 treatment decreased the intracellular Na(+)accumulation under salinity stress, suggesting that enhancement of SOS1-dependent Na(+)efflux contributes to increased high-salinity stress tolerance caused by Ky-2 treatment. PMID:26657894

  20. Histone deacetylase inhibitors modulate KATP subunit transcription in HL-1 cardiomyocytes through effects on cholesterol homeostasis

    PubMed Central

    Fatima, Naheed; Cohen, Devin C.; Sukumar, Gauthaman; Sissung, Tristan M.; Schooley, James F.; Haigney, Mark C.; Claycomb, William C.; Cox, Rachel T.; Dalgard, Clifton L.; Bates, Susan E.; Flagg, Thomas P.

    2015-01-01

    Histone deacetylase inhibitors (HDIs) are under investigation for the treatment of a number of human health problems. HDIs have proven therapeutic value in refractory cases of cutaneous T-cell lymphoma. Electrocardiographic ST segment morphological changes associated with HDIs were observed during development. Because ST segment morphology is typically linked to changes in ATP sensitive potassium (KATP) channel activity, we tested the hypothesis that HDIs affect cardiac KATP channel subunit expression. Two different HDIs, romidepsin and trichostatin A, caused ~20-fold increase in SUR2 (Abcc9) subunit mRNA expression in HL-1 cardiomyocytes. The effect was specific for the SUR2 subunit as neither compound causes a marked change in SUR1 (Abcc8) expression. Moreover, the effect was cell specific as neither HDI markedly altered KATP subunit expression in MIN6 pancreatic β-cells. We observe significant enrichment of the H3K9Ac histone mark specifically at the SUR2 promoter consistent with the conclusion that chromatin remodeling at this locus plays a role in increasing SUR2 gene expression. Unexpectedly, however, we also discovered that HDI-dependent depletion of cellular cholesterol is required for the observed effects on SUR2 expression. Taken together, the data in the present study demonstrate that KATP subunit expression can be epigenetically regulated in cardiomyocytes, defines a role for cholesterol homeostasis in mediating epigenetic regulation and suggests a potential molecular basis for the cardiac effects of the HDIs. PMID:26321954

  1. tert-Butylcarbamate-containing histone deacetylase inhibitors: apoptosis induction, cytodifferentiation, and antiproliferative activities in cancer cells.

    PubMed

    Valente, Sergio; Trisciuoglio, Daniela; Tardugno, Maria; Benedetti, Rosaria; Labella, Donatella; Secci, Daniela; Mercurio, Ciro; Boggio, Roberto; Tomassi, Stefano; Di Maro, Salvatore; Novellino, Ettore; Altucci, Lucia; Del Bufalo, Donatella; Mai, Antonello; Cosconati, Sandro

    2013-05-01

    Herein we report novel pyrrole- and benzene-based hydroxamates (8, 10) and 2'-aminoanilides (9, 11) bearing the tert-butylcarbamate group at the CAP moiety as histone deacetylase (HDAC) inhibitors. Compounds 8 b and 10 c selectively inhibited HDAC6 at the nanomolar level, whereas the other hydroxamates effected an increase in acetyl-α-tubulin levels in human acute myeloid leukemia U937 cells. In the same cell line, compounds 8 b and 10 c elicited 18.4 and 21.4 % apoptosis, respectively (SAHA: 16.9 %), and the pyrrole anilide 9 c displayed the highest cytodifferentiating effect (90.9 %). In tests against a wide range of various cancer cell lines to determine its antiproliferative effects, compound 10 c exhibited growth inhibition from sub-micromolar (neuroblastoma LAN-5 and SH-SY5Y cells, chronic myeloid leukemia K562 cells) to low-micromolar (lung H1299 and A549, colon HCT116 and HT29 cancer cells) concentrations. In HT29 cells, 10 c increased histone H3 acetylation, and decreased the colony-forming potential of the cancer cells by up to 60 %. PMID:23526814

  2. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation

    PubMed Central

    Haggarty, Stephen J.; Koeller, Kathryn M.; Wong, Jason C.; Grozinger, Christina M.; Schreiber, Stuart L.

    2003-01-01

    Protein acetylation, especially histone acetylation, is the subject of both research and clinical investigation. At least four small-molecule histone deacetylase inhibitors are currently in clinical trials for the treatment of cancer. These and other inhibitors also affect microtubule acetylation. A multidimensional, chemical genetic screen of 7,392 small molecules was used to discover “tubacin,” which inhibits α-tubulin deacetylation in mammalian cells. Tubacin does not affect the level of histone acetylation, gene-expression patterns, or cell-cycle progression. We provide evidence that class II histone deacetylase 6 (HDAC6) is the intracellular target of tubacin. Only one of the two catalytic domains of HDAC6 possesses tubulin deacetylase activity, and only this domain is bound by tubacin. Tubacin treatment did not affect the stability of microtubules but did decrease cell motility. HDAC6 overexpression disrupted the localization of p58, a protein that mediates binding of Golgi elements to microtubules. Our results highlight the role of α-tubulin acetylation in mediating the localization of microtubule-associated proteins. They also suggest that small molecules that selectively inhibit HDAC6-mediated α-tubulin deacetylation, a first example of which is tubacin, might have therapeutic applications as antimetastatic and antiangiogenic agents. PMID:12677000

  3. Epigenetic suppression of the antitumor cytotoxicity of NK cells by histone deacetylase inhibitor valproic acid

    PubMed Central

    Shi, Xiumin; Li, Min; Cui, Meizi; Niu, Chao; Xu, Jianting; Zhou, Lei; Li, Wei; Gao, Yushun; Kong, Weisheng; Cui, Jiuwei; Hu, Jifan; Jin, Haofan

    2016-01-01

    Natural killer (NK) cells play an essential role in the fight against tumor development. The therapeutic use of autologous NK cells has been exploited to treat human malignancies, yet only limited antitumor activity is observed in cancer patients. In this study, we sought to augment the antitumor activity of NK cells using epigenetic approaches. Four small molecules that have been known to promote epigenetic reprogramming were tested for their ability to enhance the activity of NK cells. Using a tumor cell lysis assay, we found that the DNA demethylating agent 5-azacytidine and vitamin C did not significantly affect the tumor killing ability of NK cells. The thyroid hormone triiodothyronine (T3) slightly increased the activity of NK cells. The histone deacetylase inhibitor valproic acid (VPA), however, inhibited NK cell lytic activity against leukemic cells in a dose-dependent manner. Pretreatment using VPA reduced IFNγ secretion, impaired CD107a degranulation, and induced apoptosis by activating the PD-1/PD-L1 pathway. VPA downregulated the expression of the activating receptor NKG2D (natural-killer group 2, member D) by inducing histone K9 hypermethylation and DNA methylation in the gene promoter. Histone deacetylase inhibitors have been developed as anticancer agents for use as monotherapies or in combination with other anticancer therapies. Our data suggest that the activity of histone deacetylase inhibitors on NK cell activity should be considered in drug development. PMID:27152238

  4. Human HDAC7 Harbors a Class IIa Histone Deacetylase-specific Zinc Binding Motif and Cryptic Deacetylase Activity

    SciTech Connect

    Schuetz, Anja; Min, Jinrong; Allali-Hassani, Abdellah; Schapira, Matthieu; Shuen, Michael; Loppnau, Peter; Mazitschek, Ralph; Kwiatkowski, Nick P.; Lewis, Timothy A.; Maglathin, Rebecca L.; McLean, Thomas H.; Bochkarev, Alexey; Plotnikov, Alexander N.; Vedadi, Masoud; Arrowsmith, Cheryl H.

    2010-10-18

    Histone deacetylases (HDACs) are protein deacetylases that play a role in repression of gene transcription and are emerging targets in cancer therapy. Here, we characterize the structure and enzymatic activity of the catalytic domain of human HDAC7 (cdHDAC7). Although HDAC7 normally exists as part of a multiprotein complex, we show that cdHDAC7 has a low level of deacetylase activity which can be inhibited by known HDAC inhibitors. The crystal structures of human cdHDAC7 and its complexes with two hydroxamate inhibitors are the first structures of the catalytic domain of class IIa HDACs and demonstrate significant differences with previously reported class I and class IIb-like HDAC structures. We show that cdHDAC7 has an additional class IIa HDAC-specific zinc binding motif adjacent to the active site which is likely to participate in substrate recognition and protein-protein interaction and may provide a site for modulation of activity. Furthermore, a different active site topology results in modified catalytic properties and in an enlarged active site pocket. Our studies provide mechanistic insights into class IIa HDACs and facilitate the design of specific modulators.

  5. Histone deacetylase inhibitors and aspirin interact synergistically to induce cell death in ovarian cancer cells.

    PubMed

    Sonnemann, Jürgen; Hüls, Isabel; Sigler, Michael; Palani, Chithra D; Hong, Le Thi Thu; Völker, Uwe; Kroemer, Heyo K; Beck, James F

    2008-07-01

    Histone deacetylase inhibitors (HDIs) as well as non-steroidal anti-inflammatory drugs including aspirin show promise as antineoplastic agents. The treatment with both HDIs and aspirin can result in hyperacetylation of proteins. In this study, we investigated whether HDIs and aspirin interacted in inducing anticancer activity and histone acetylation. We found that the HDIs, suberoylanilide hydroxamic acid and sodium butyrate, and aspirin cooperated to induce cell death in the ovarian cancer cell line, A2780. The effect was synergistic, as evidenced by CI-isobologram analysis. However, aspirin had no effect on histone acetylation, neither in the absence nor presence of HDIs. To gain insight into the mechanism underlying the synergistic action of HDIs and aspirin, we employed the deacetylated metabolite of aspirin, salicylic acid, and the cyclooxygenase-1- and -2-selective inhibitors, SC-560 and NS-398, respectively. We found that HDIs and salicylic acid interacted synergistically, albeit less efficiently than HDIs and aspirin, to induce cancer cell death, suggesting that the acetyl and the salicyl moiety contributed to the cooperative interaction of aspirin with HDIs. SC-560 and NS-398 had little effect both when applied alone or in conjunction with HDIs, indicating that the combinatorial effect of HDIs and aspirin was not the result of cyclo-oxygenase inhibition. In conclusion, our study demonstrates that HDIs and aspirin synergize to induce cancer cell death and, thus, provides a rationale for a more in-depth exploration into the potential of combining HDIs and aspirin as a strategy for anticancer therapy. PMID:18575740

  6. Dynamic phosphorylation of Histone Deacetylase 1 by Aurora kinases during mitosis regulates zebrafish embryos development

    PubMed Central

    Loponte, Sara; Segré, Chiara V.; Senese, Silvia; Miccolo, Claudia; Santaguida, Stefano; Deflorian, Gianluca; Citro, Simona; Mattoscio, Domenico; Pisati, Federica; Moser, Mirjam A.; Visintin, Rosella; Seiser, Christian; Chiocca, Susanna

    2016-01-01

    Histone deacetylases (HDACs) catalyze the removal of acetyl molecules from histone and non-histone substrates playing important roles in chromatin remodeling and control of gene expression. Class I HDAC1 is a critical regulator of cell cycle progression, cellular proliferation and differentiation during development; it is also regulated by many post-translational modifications (PTMs). Herein we characterize a new mitosis-specific phosphorylation of HDAC1 driven by Aurora kinases A and B. We show that this phosphorylation affects HDAC1 enzymatic activity and it is critical for the maintenance of a proper proliferative and developmental plan in a complex organism. Notably, we find that Aurora-dependent phosphorylation of HDAC1 regulates histone acetylation by modulating the expression of genes directly involved in the developing zebrafish central nervous system. Our data represent a step towards the comprehension of HDAC1 regulation by its PTM code, with important implications in unravelling its roles both in physiology and pathology. PMID:27458029

  7. Histone Deacetylase Inhibition–Mediated Differentiation of RGC-5 Cells and Interaction with Survival

    PubMed Central

    Schwechter, Brandon R.; Millet, Lucia E.; Levin, Leonard A.

    2008-01-01

    PURPOSE The acetylation state of histones is modulated by histone deacetylase (HDAC) and histone acetyltransferase and is an important component in regulating gene transcription, including neuronal differentiation. The authors studied the relationship between histone acetylation and the differentiation and survival of the RGC-5 cell line and compared it with nontranscriptional-dependent differentiation with staurosporine. METHODS The retinal ganglion cell line RGC-5 was treated with trichostatin A (TSA), other HDAC inhibitors, and staurosporine; differentiation, neuritogenesis, neurotrophic factor dependence, and dependence on RNA transcription were assessed. RESULTS TSA caused significant differentiation and neuritogenesis. Differences between HDAC inhibition and staurosporine differentiation included the proportion of differentiated cells, cell viability, cell morphology, and transcriptional dependence. HDAC inhibition, but not staurosporine differentiation, resulted in RGC-5 cells that were neurotrophic factor dependent. CONCLUSIONS These results implicate two different mechanisms for RGC-5 differentiation, with a common downstream effect on neurite outgrowth but a differential effect on neurotrophic factor dependence. PMID:17525221

  8. Dynamic phosphorylation of Histone Deacetylase 1 by Aurora kinases during mitosis regulates zebrafish embryos development.

    PubMed

    Loponte, Sara; Segré, Chiara V; Senese, Silvia; Miccolo, Claudia; Santaguida, Stefano; Deflorian, Gianluca; Citro, Simona; Mattoscio, Domenico; Pisati, Federica; Moser, Mirjam A; Visintin, Rosella; Seiser, Christian; Chiocca, Susanna

    2016-01-01

    Histone deacetylases (HDACs) catalyze the removal of acetyl molecules from histone and non-histone substrates playing important roles in chromatin remodeling and control of gene expression. Class I HDAC1 is a critical regulator of cell cycle progression, cellular proliferation and differentiation during development; it is also regulated by many post-translational modifications (PTMs). Herein we characterize a new mitosis-specific phosphorylation of HDAC1 driven by Aurora kinases A and B. We show that this phosphorylation affects HDAC1 enzymatic activity and it is critical for the maintenance of a proper proliferative and developmental plan in a complex organism. Notably, we find that Aurora-dependent phosphorylation of HDAC1 regulates histone acetylation by modulating the expression of genes directly involved in the developing zebrafish central nervous system. Our data represent a step towards the comprehension of HDAC1 regulation by its PTM code, with important implications in unravelling its roles both in physiology and pathology. PMID:27458029

  9. Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton

    PubMed Central

    Mwakwari, Sandra C.; Guerrant, William; Patil, Vishal; Khan, Shabana I.; Tekwani, Babu L.; Gurard-Levin, Zachary A.; Mrksich, Milan; Oyelere, Adegboyega K.

    2010-01-01

    Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap-groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part due to development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDAC 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme's outer rim and the inhibitors’ macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity. PMID:20669972

  10. Histone deacetylase inhibitor givinostat: the small-molecule with promising activity against therapeutically challenging haematological malignancies.

    PubMed

    Ganai, Shabir Ahmad

    2016-08-01

    Histone acetyl transferases and histone deacetylases (HDACs) are counteracting epigenetic enzymes regulating the turnover of histone acetylation thereby regulating transcriptional events in a precise manner. Deregulation of histone acetylation caused by aberrant expression of HDACs plays a key role in tumour onset and progression making these enzymes as candidate targets for anticancer drugs and therapy. Small-molecules namely histone deacetylase inhibitors (HDACi) modulating the biological function of HDACs have shown multiple biological effects including differentiation, cell cycle arrest and apoptosis in tumour models. HDACi in general have been described in plethora of reviews with respect to various cancers. However, no review article is available describing thoroughly the role of inhibitor givinostat (ITF2357 or [6-(diethylaminomethyl) naphthalen-2-yl] methyl N-[4-(hydroxycarbamoyl) phenyl] carbamate) in haematological malignancies. Thus, the present review explores the intricate role of novel inhibitor givinostat in the defined malignancies including multiple myeloma, acute myelogenous leukaemia, Hodgkin's and non-Hodgkin's lymphoma apart from myeloproliferative neoplasms. The distinct molecular mechanisms triggered by this small-molecule inhibitor in these cancers to exert cytotoxic effect have also been dealt with. The article also highlights the combination strategy that can be used for enhancing the therapeutic efficiency of this inhibitor in the upcoming future. PMID:27121910

  11. The C. elegans histone deacetylase HDA-1 is required for cell migration and axon pathfinding.

    PubMed

    Zinovyeva, Anna Y; Graham, Serena M; Cloud, Veronica J; Forrester, Wayne C

    2006-01-01

    Histone proteins play integral roles in chromatin structure and function. Histones are subject to several types of posttranslational modifications, including acetylation, which can produce transcriptional activation. The converse, histone deacetylation, is mediated by histone deacetylases (HDACs) and often is associated with transcriptional silencing. We identified a new mutation, cw2, in the Caenorhabditis elegans hda-1 gene, which encodes a histone deacetylase. Previous studies showed that a mutation in hda-1, e1795, or reduction of hda-1 RNA by RNAi causes defective vulval and gonadal development leading to sterility. The hda-1(cw2) mutation causes defective vulval development and reduced fertility, like hda-1(e1795), albeit with reduced severity. Unlike the previously reported hda-1 mutation, hda-1(cw2) mutants are viable as homozygotes, although many die as embryos or larvae, and are severely uncoordinated. Strikingly, in hda-1(cw2) mutants, axon pathfinding is defective; specific axons often appear to wander randomly or migrate in the wrong direction. In addition, the long range migrations of three neuron types and fasciculation of the ventral nerve cord are defective. Together, our studies define a new role for HDA-1 in nervous system development, and provide the first evidence for HDAC function in regulating neuronal axon guidance. PMID:16313898

  12. Elevated nuclear sphingoid base-1-phosphates and decreased histone deacetylase activity after fumonisin B1 treatment in mouse embryonic fibroblasts.

    PubMed

    Gardner, Nicole M; Riley, Ronald T; Showker, Jency L; Voss, Kenneth A; Sachs, Andrew J; Maddox, Joyce R; Gelineau-van Waes, Janee B

    2016-05-01

    Fumonisin B1 (FB1) is a mycotoxin produced by a common fungal contaminant of corn. Administration of FB1 to pregnant LM/Bc mice induces exencephaly in embryos, and ingestion of FB1-contaminated food during early pregnancy is associated with increased risk for neural tube defects (NTDs) in humans. FB1 inhibits ceramide synthase enzymes in sphingolipid biosynthesis, causing sphinganine (Sa) and bioactive sphinganine-1-phosphate (Sa1P) accumulation in blood, cells, and tissues. Sphingosine kinases (Sphk) phosphorylate Sa to form Sa1P. Upon activation, Sphk1 associates primarily with the plasma membrane, while Sphk2 is found predominantly in the nucleus. In cells over-expressing Sphk2, accumulation of Sa1P in the nuclear compartment inhibits histone deacetylase (HDAC) activity, causing increased acetylation of histone lysine residues. In this study, FB1 treatment in LM/Bc mouse embryonic fibroblasts (MEFs) resulted in significant accumulation of Sa1P in nuclear extracts relative to cytoplasmic extracts. Elevated nuclear Sa1P corresponded to decreased histone deacetylase (HDAC) activity and increased histone acetylation at H2BK12, H3K9, H3K18, and H3K23. Treatment of LM/Bc MEFs with a selective Sphk1 inhibitor, PF-543, or with ABC294640, a selective Sphk2 inhibitor, significantly reduced nuclear Sa1P accumulation after FB1, although Sa1P levels remained significantly increased relative to basal levels. Concurrent treatment with both PF-543 and ABC294640 prevented nuclear accumulation of Sa1P in response to FB1. Other HDAC inhibitors are known to cause NTDs, so these results suggest that FB1-induced disruption of sphingolipid metabolism leading to nuclear Sa1P accumulation, HDAC inhibition, and histone hyperacetylation is a potential mechanism for FB1-induced NTDs. PMID:26905748

  13. Inhibition of Histone Deacetylase 3 Causes Replication Stress in Cutaneous T Cell Lymphoma

    PubMed Central

    Wells, Christina E.; Bhaskara, Srividya; Stengel, Kristy R.; Zhao, Yue; Sirbu, Bianca; Chagot, Benjamin; Cortez, David; Khabele, Dineo; Chazin, Walter J.; Cooper, Andrew; Jacques, Vincent; Rusche, James; Eischen, Christine M.; McGirt, Laura Y.; Hiebert, Scott W.

    2013-01-01

    Given the fundamental roles of histone deacetylases (HDACs) in the regulation of DNA repair, replication, transcription and chromatin structure, it is fitting that therapies targeting HDAC activities are now being explored as anti-cancer agents. In fact, two histone deacetylase inhibitors (HDIs), SAHA and Depsipeptide, are FDA approved for single-agent treatment of refractory cutaneous T cell lymphoma (CTCL). An important target of these HDIs, histone deacetylase 3 (HDAC3), regulates processes such as DNA repair, metabolism, and tumorigenesis through the regulation of chromatin structure and gene expression. Here we show that HDAC3 inhibition using a first in class selective inhibitor, RGFP966, resulted in decreased cell growth in CTCL cell lines due to increased apoptosis that was associated with DNA damage and impaired S phase progression. Through isolation of proteins on nascent DNA (iPOND), we found that HDAC3 was associated with chromatin and is present at and around DNA replication forks. DNA fiber labeling analysis showed that inhibition of HDAC3 resulted in a significant reduction in DNA replication fork velocity within the first hour of drug treatment. These results suggest that selective inhibition of HDAC3 could be useful in treatment of CTCL by disrupting DNA replication of the rapidly cycling tumor cells, ultimately leading to cell death. PMID:23894374

  14. Genistein cooperates with the histone deacetylase inhibitor vorinostat to induce cell death in prostate cancer cells

    PubMed Central

    2012-01-01

    Background Among American men, prostate cancer is the most common, non-cutaneous malignancy that accounted for an estimated 241,000 new cases and 34,000 deaths in 2011. Previous studies have suggested that Wnt pathway inhibitory genes are silenced by CpG hypermethylation, and other studies have suggested that genistein can demethylate hypermethylated DNA. Genistein is a soy isoflavone with diverse effects on cellular proliferation, survival, and gene expression that suggest it could be a potential therapeutic agent for prostate cancer. We undertook the present study to investigate the effects of genistein on the epigenome of prostate cancer cells and to discover novel combination approaches of other compounds with genistein that might be of translational utility. Here, we have investigated the effects of genistein on several prostate cancer cell lines, including the ARCaP-E/ARCaP-M model of the epithelial to mesenchymal transition (EMT), to analyze effects on their epigenetic state. In addition, we investigated the effects of combined treatment of genistein with the histone deacetylase inhibitor vorinostat on survival in prostate cancer cells. Methods Using whole genome expression profiling and whole genome methylation profiling, we have determined the genome-wide differences in genetic and epigenetic responses to genistein in prostate cancer cells before and after undergoing the EMT. Also, cells were treated with genistein, vorinostat, and combination treatment, where cell death and cell proliferation was determined. Results Contrary to earlier reports, genistein did not have an effect on CpG methylation at 20 μM, but it did affect histone H3K9 acetylation and induced increased expression of histone acetyltransferase 1 (HAT1). In addition, genistein also had differential effects on survival and cooperated with the histone deacteylase inhibitor vorinostat to induce cell death and inhibit proliferation. Conclusion Our results suggest that there are a number of

  15. Anti-tumor activity of N-hydroxy-7-(2-naphthylthio) heptanomide, a novel histone deacetylase inhibitor

    SciTech Connect

    Kim, Dong Hoon; Lee, Jiyong; Kim, Kyung Noo; Kim, Hye Jin; Jeung, Hei Cheul; Chung, Hyun Cheol; Kwon, Ho Jeong . E-mail: kwonhj@yonsei.ac.kr

    2007-04-27

    Histone deacetylase (HDAC), a key enzyme in gene expression and carcinogenesis, is considered an attractive target molecule for cancer therapy. Here, we report a new synthetic small molecule, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), as a HDAC inhibitor with anti-tumor activity both in vitro and in vivo. The compound inhibited HDAC enzyme activity as well as proliferation of human fibrosarcoma cells (HT1080) in vitro. Treatment of cells with HNHA elicited histone hyperacetylation leading to an up-regulation of p21 transcription, cell cycle arrest, and an inhibition of HT1080 cell invasion. Moreover, HNHA effectively inhibited the growth of tumor tissue in a mouse xenograph assay in vivo. Together, these data demonstrate that this novel HDAC inhibitor could be developed as a potential anti-tumor agent targeting HDAC.

  16. HISTONE DEACETYLASE 9 represses seedling traits in Arabidopsis thaliana dry seeds.

    PubMed

    van Zanten, Martijn; Zöll, Christian; Wang, Zhi; Philipp, Christina; Carles, Annaick; Li, Yong; Kornet, Noortje G; Liu, Yongxiu; Soppe, Wim J J

    2014-11-01

    Plant life is characterized by major phase changes. We studied the role of histone deacetylase (HDAC) activity in the transition from seed to seedling in Arabidopsis. Pharmacological inhibition of HDAC stimulated germination of freshly harvested seeds. Subsequent analysis revealed that histone deacetylase 9 (hda9) mutant alleles displayed reduced seed dormancy and faster germination than wild-type plants. Transcriptome meta-analysis comparisons between the hda9 dry seed transcriptome and published datasets demonstrated that transcripts of genes that are induced during imbibition in wild-type prematurely accumulated in hda9-1 dry seeds. This included several genes associated with photosynthesis and photoautotrophic growth such as RuBisCO and RuBisCO activase (RCA). Chromatin immunoprecipitation experiments demonstrated enhanced histone acetylation levels at their loci in young hda9-1 seedlings. Our observations suggest that HDA9 negatively influences germination and is involved in the suppression of seedling traits in dry seeds, probably by transcriptional repression via histone deacetylation. Accordingly, HDA9 transcript is abundant in dry seeds and becomes reduced during imbibition in wild-type seeds. The proposed function of HDA9 is opposite to that of its homologous genes HDA6 and HDA19, which have been reported to repress embryonic properties in germinated seedlings. PMID:25146719

  17. Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats.

    PubMed

    Castino, Matthew R; Cornish, Jennifer L; Clemens, Kelly J

    2015-01-01

    Chromatin remodelling is integral to the formation of long-term memories. Recent evidence suggests that histone modification may play a role in the persistence of memories associated with drug use. The present series of experiments aimed to examine the effect of histone deacetylase (HDAC) inhibition on the extinction and reinstatement of nicotine self-administration. Rats were trained to intravenously self-administer nicotine for 12 days on a fixed-ratio 1 schedule. In Experiment 1, responding was then extinguished through removal of nicotine and response-contingent cues. After each extinction session, the HDAC inhibitor, sodium butyrate (NaB), was administered immediately, or six hours after each session. In Experiment 2, response-contingent cues remained available across extinction to increase rates of responding during this phase, and NaB was administered immediately after the session. Finally, in Experiment 3, the effect of NaB treatment on extinction of responding for sucrose pellets was assessed. Across all experiments reinstatement to the cue and/or the reward itself was then tested. In the first experiment, treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately, but not six hours after each extinction session. When administered after cue-extinction (Expt. 2), NaB treatment specifically facilitated the rate of extinction across sessions, indicating that HDAC inhibition enhanced consolidation of the extinction memory. In contrast, there was no effect of NaB on the extinction and reinstatement of sucrose-seeking (Expt. 3), indicating that the observed effects are specific to a drug context. These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction. PMID:25880762

  18. Role of histone deacetylases(HDACs) in progression and reversal of liver fibrosis.

    PubMed

    Li, Xing; Wu, Xiao-Qin; Xu, Tao; Li, Xiao-Feng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun

    2016-09-01

    Liver fibrosis refers to a reversible wound healing process response to chronic liver injuries. Activation of hepatic stellate cells (HSCs) is closely correlated with the development of liver fibrosis. Histone deacetylases(HDACs) determine the acetylation levels of core histones to modulate expression of genes. To demonstrate the link between HDACs and liver fibrosis, CCl4-induced mouse liver fibrosis model and its spontaneous reversal model were established. Results of the current study demonstrated that deregulation of liver HDACs may involved in the development of liver fibrosis. Among 11 HDACs tested in our study (Class I, II, and IV HDACs), expression of HDAC2 was maximally increased in CCl4-induced fibrotic livers but decreased after spontaneous recovery. Moreover, expression of HDAC2 was elevated in human liver fibrotic tissues. In this regard, the potential role of HDAC2 in liver fibrosis was further evaluated. Our results showed that administration of HSC-T6 cells with transforming growth factor-beta1 (TGF-β1) resulted in an increase of HDAC2 protein expression in dose- and time-dependent manners. Moreover, HDAC2 deficiency inhibited HSC-T6 cell proliferation and activation induced by TGF-β1. More importantly, the present study showed HDAC2 may regulate HSCs activation by suppressing expression of Smad7, which is a negative modulator in HSCs activation and liver fibrosis. Collectively, these observations revealed that HDAC2 may play a pivotal role in HSCs activation and liver fibrosis while deregulation of HDACs may serve as a novel mechanism underlying liver fibrosis. PMID:27396813

  19. Inhibition of Histone Deacetylases Facilitates Extinction and Attenuates Reinstatement of Nicotine Self-Administration in Rats

    PubMed Central

    Castino, Matthew R.; Cornish, Jennifer L.; Clemens, Kelly J.

    2015-01-01

    Chromatin remodelling is integral to the formation of long-term memories. Recent evidence suggests that histone modification may play a role in the persistence of memories associated with drug use. The present series of experiments aimed to examine the effect of histone deacetylase (HDAC) inhibition on the extinction and reinstatement of nicotine self-administration. Rats were trained to intravenously self-administer nicotine for 12 days on a fixed-ratio 1 schedule. In Experiment 1, responding was then extinguished through removal of nicotine and response-contingent cues. After each extinction session, the HDAC inhibitor, sodium butyrate (NaB), was administered immediately, or six hours after each session. In Experiment 2, response-contingent cues remained available across extinction to increase rates of responding during this phase, and NaB was administered immediately after the session. Finally, in Experiment 3, the effect of NaB treatment on extinction of responding for sucrose pellets was assessed. Across all experiments reinstatement to the cue and/or the reward itself was then tested. In the first experiment, treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately, but not six hours after each extinction session. When administered after cue-extinction (Expt. 2), NaB treatment specifically facilitated the rate of extinction across sessions, indicating that HDAC inhibition enhanced consolidation of the extinction memory. In contrast, there was no effect of NaB on the extinction and reinstatement of sucrose-seeking (Expt. 3), indicating that the observed effects are specific to a drug context. These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction. PMID:25880762

  20. Histone deacetylase inhibitor screening identifies HC toxin as the most effective in intrahepatic cholangiocarcinoma cells.

    PubMed

    Zhou, Wenjie; Chen, Xiaoxun; He, Ke; Xiao, Jinfeng; Duan, Xiaopeng; Huang, Rui; Xia, Zhenglin; He, Jingliang; Zhang, Jinqian; Xiang, Guoan

    2016-05-01

    Histone deacetylases (HDACs) are highly expressed in intrahepatic cholangiocarcinoma (ICC) and are associated with poor prognosis of these patients. The aim of the present study was to explore the inhibitory effects of HDAC inhibitors on ICC cells and identify effective and sensitive drugs for ICC. Effects of 34 HDAC inhibitors were screened through two rounds of cell viability assays, and HC toxin, a cyclic tetrapeptide first isolated from the secondary metabolite of Helminthosporium carbonum, exhibited an antitumor activity superior to that of the other HDAC inhibitors and gemcitabine. The mechanisms involved in the inhibitory effects of HC toxin on CCLP-1 cells were investigated by cell counting, colony formation assay, cell morphological observation, real-time PCR, western blotting and flow cytometry. It was demonstrated that HC toxin inhibited the cell proliferation and clone formation ability of the CCLP-1 cells. HC toxin increased the acetyl-histone H4 level and this was associated with the inhibitory effect of HC toxin on the CCLP-1 cells. We also found that HC toxin reduced the level of HDAC1 protein in a post-transcriptional manner. Morphological observation showed multiple morphological changes and indicated the possibility of cell differentiation owing to HC toxin. With increasing concentration of HC toxin, the cell cycle was gradually arrested at the G0/G1 stage and the percentage of apoptotic cells increased which was not mainly through the caspase-3-dependent ways. These results indicated that HC toxin was the most effective among the various HDAC inhibitors with multiple functions in the suppression of ICC in vitro. Thus, HC may be a potential chemotherapeutic for ICC. PMID:26935789

  1. Histone deacetylase inhibitor screening identifies HC toxin as the most effective in intrahepatic cholangiocarcinoma cells

    PubMed Central

    ZHOU, WENJIE; CHEN, XIAOXUN; HE, KE; XIAO, JINFENG; DUAN, XIAOPENG; HUANG, RUI; XIA, ZHENGLIN; HE, JINGLIANG; ZHANG, JINQIAN; XIANG, GUOAN

    2016-01-01

    Histone deacetylases (HDACs) are highly expressed in intrahepatic cholangiocarcinoma (ICC) and are associated with poor prognosis of these patients. The aim of the present study was to explore the inhibitory effects of HDAC inhibitors on ICC cells and identify effective and sensitive drugs for ICC. Effects of 34 HDAC inhibitors were screened through two rounds of cell viability assays, and HC toxin, a cyclic tetrapeptide first isolated from the secondary metabolite of Helminthosporium carbonum, exhibited an antitumor activity superior to that of the other HDAC inhibitors and gemcitabine. The mechanisms involved in the inhibitory effects of HC toxin on CCLP-1 cells were investigated by cell counting, colony formation assay, cell morphological observation, real-time PCR, western blotting and flow cytometry. It was demonstrated that HC toxin inhibited the cell proliferation and clone formation ability of the CCLP-1 cells. HC toxin increased the acetyl-histone H4 level and this was associated with the inhibitory effect of HC toxin on the CCLP-1 cells. We also found that HC toxin reduced the level of HDAC1 protein in a post-transcriptional manner. Morphological observation showed multiple morphological changes and indicated the possibility of cell differentiation owing to HC toxin. With increasing concentration of HC toxin, the cell cycle was gradually arrested at the G0/G1 stage and the percentage of apoptotic cells increased which was not mainly through the caspase-3-dependent ways. These results indicated that HC toxin was the most effective among the various HDAC inhibitors with multiple functions in the suppression of ICC in vitro. Thus, HC may be a potential chemotherapeutic for ICC. PMID:26935789

  2. Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators

    PubMed Central

    Kaliman, Perla; Álvarez-López, María Jesús; Cosín-Tomás, Marta; Rosenkranz, Melissa A.; Lutz, Antoine; Davidson, Richard J.

    2013-01-01

    BACKGROUND A growing body of research shows that mindfulness meditation can alter neural, behavioral and biochemical processes. However, the mechanisms responsible for such clinically relevant effects remain elusive. METHODS Here we explored the impact of a day of intensive practice of mindfulness meditation in experienced subjects (n= 19) on the expression of circadian, chromatin modulatory and inflammatory genes in peripheral blood mononuclear cells (PBMCs). In parallel, we analyzed a control group of subjects with no meditation experience who engaged in leisure activities in the same environment (n= 21). PBMCs from all participants were obtained before (t1) and after (t2) the intervention (t2-t1= 8 hours) and gene expression was analyzed using custom pathway focused quantitative-real time PCR assays. Both groups were also presented with the Trier Social Stress Test (TSST). RESULTS Core clock gene expression at baseline (t1) was similar between groups and their rhythmicity was not influenced in meditators by the intensive day of practice. Similarly, we found that all the epigenetic regulatory enzymes and inflammatory genes analyzed exhibited similar basal expression levels in the two groups. In contrast, after the brief intervention we detected reduced expression of histone deacetylase genes (HDAC2, 3 and 9), alterations in global modification of histones (H4ac; H3K4me3) and decreased expression of pro-inflammatory genes (RIPK2 and COX2) in meditators compared with controls. We found that the expression of RIPK2 and HDAC2 genes was associated with a faster cortisol recovery to the TSST in both groups. CONCLUSIONS The regulation of HDACs and inflammatory pathways may represent some of the mechanisms underlying the therapeutic potential of mindfulness-based interventions. Our findings set the foundation for future studies to further assess meditation strategies for the treatment of chronic inflammatory conditions. PMID:24485481

  3. Assembly of the SMRT–histone deacetylase 3 repression complex requires the TCP-1 ring complex

    PubMed Central

    Guenther, Matthew G.; Yu, Jiujiu; Kao, Gary D.; Yen, Tim J.; Lazar, Mitchell A.

    2002-01-01

    The acetylation of histone tails is a primary determinant of gene activity. Histone deacetylase 3 (HDAC3) requires the nuclear receptor corepressor SMRT for HDAC enzyme activity. Here we report that HDAC3 interacts with SMRT only after priming by cellular chaperones including the TCP-1 ring complex (TRiC), which is required for proper folding of HDAC3 in an ATP-dependent process. SMRT displaces TRiC from HDAC3, yielding an active HDAC enzyme. The SMRT–HDAC3 repression complex thus joins the VHL–elongin BC tumor suppression complex and the cyclin E–Cdk2 cell cycle regulation complex as critical cellular machines requiring TRiC for proper assembly and function. The strict control of HDAC3 activity underscores the cellular imperative that histone deacetylation occur only in targeted regions of the genome. PMID:12502735

  4. Plants Release Precursors of Histone Deacetylase Inhibitors to Suppress Growth of Competitors.

    PubMed

    Venturelli, Sascha; Belz, Regina G; Kämper, Andreas; Berger, Alexander; von Horn, Kyra; Wegner, André; Böcker, Alexander; Zabulon, Gérald; Langenecker, Tobias; Kohlbacher, Oliver; Barneche, Fredy; Weigel, Detlef; Lauer, Ulrich M; Bitzer, Michael; Becker, Claude

    2015-11-01

    To secure their access to water, light, and nutrients, many plant species have developed allelopathic strategies to suppress competitors. To this end, they release into the rhizosphere phytotoxic substances that inhibit the germination and growth of neighbors. Despite the importance of allelopathy in shaping natural plant communities and for agricultural production, the underlying molecular mechanisms are largely unknown. Here, we report that allelochemicals derived from the common class of cyclic hydroxamic acid root exudates directly affect the chromatin-modifying machinery in Arabidopsis thaliana. These allelochemicals inhibit histone deacetylases both in vitro and in vivo and exert their activity through locus-specific alterations of histone acetylation and associated gene expression. Our multilevel analysis collectively shows how plant-plant interactions interfere with a fundamental cellular process, histone acetylation, by targeting an evolutionarily highly conserved class of enzymes. PMID:26530086

  5. Development of N-Hydroxycinnamamide-Based Histone Deacetylase Inhibitors with an Indole-Containing Cap Group

    PubMed Central

    2013-01-01

    A novel series of histone deacetylase inhibitors combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment was designed and synthesized. Several compounds (17c, 17g, 17h, 17j, and 17k) exhibited comparable, even superior, total HDACs inhibitory activity and in vitro antiproliferative activities relative to the approved drug SAHA. A representative compound 17a with moderate HDACs inhibition was progressed to isoform selectivity profile, Western blot analysis, and in vivo antitumor assay. Although HDACs isoform selectivity of 17a was similar to that of SAHA, our Western blot results indicated that intracellular effects of 17a at 1 μM were class I selective. It was noteworthy that the effect on histone H4 acetylation of SAHA decreased with time, while the effect on histone H4 acetylation of 17a was maintained and even increased. Most importantly, compound 17a exhibited promising in vivo antitumor activity in a U937 xenograft model. PMID:23493449

  6. Plants Release Precursors of Histone Deacetylase Inhibitors to Suppress Growth of Competitors[OPEN

    PubMed Central

    Venturelli, Sascha; Belz, Regina G.; Kämper, Andreas; Berger, Alexander; von Horn, Kyra; Wegner, André; Böcker, Alexander; Zabulon, Gérald; Barneche, Fredy; Lauer, Ulrich M.; Bitzer, Michael

    2015-01-01

    To secure their access to water, light, and nutrients, many plant species have developed allelopathic strategies to suppress competitors. To this end, they release into the rhizosphere phytotoxic substances that inhibit the germination and growth of neighbors. Despite the importance of allelopathy in shaping natural plant communities and for agricultural production, the underlying molecular mechanisms are largely unknown. Here, we report that allelochemicals derived from the common class of cyclic hydroxamic acid root exudates directly affect the chromatin-modifying machinery in Arabidopsis thaliana. These allelochemicals inhibit histone deacetylases both in vitro and in vivo and exert their activity through locus-specific alterations of histone acetylation and associated gene expression. Our multilevel analysis collectively shows how plant-plant interactions interfere with a fundamental cellular process, histone acetylation, by targeting an evolutionarily highly conserved class of enzymes. PMID:26530086

  7. Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed

    PubMed Central

    Gryder, Berkley E; Sodji, Quaovi H; Oyelere, Adegboyega K

    2012-01-01

    Histone deacetylase inhibitors (HDACis) have now emerged as a powerful new class of small-molecule therapeutics acting through the regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. Over 490 clinical trials have been initiated in the last 10 years, culminating in the approval of two structurally distinct HDACis – SAHA (vorinostat, Zolinza™) and FK228 (romidepsin, Istodax™). However, the current HDACis have serious limitations, including ineffectively low concentrations in solid tumors and cardiac toxicity, which is hindering their progress in the clinic. Herein, we review the primary paradigms being pursued to overcome these hindrances, including HDAC isoform selectivity, localized administration, and targeting cap groups to achieve selective tissue and cell type distribution. PMID:22416777

  8. The histone deacetylase inhibiting drug Entinostat induces lipid accumulation in differentiated HepaRG cells.

    PubMed

    Nunn, Abigail D G; Scopigno, Tullio; Pediconi, Natalia; Levrero, Massimo; Hagman, Henning; Kiskis, Juris; Enejder, Annika

    2016-01-01

    Dietary overload of toxic, free metabolic intermediates leads to disrupted insulin signalling and fatty liver disease. However, it was recently reported that this pathway might not be universal: depletion of histone deacetylase (HDAC) enhances insulin sensitivity alongside hepatic lipid accumulation in mice, but the mechanistic role of microscopic lipid structure in this effect remains unclear. Here we study the effect of Entinostat, a synthetic HDAC inhibitor undergoing clinical trials, on hepatic lipid metabolism in the paradigmatic HepaRG liver cell line. Specifically, we statistically quantify lipid droplet morphology at single cell level utilizing label-free microscopy, coherent anti-Stokes Raman scattering, supported by gene expression. We observe Entinostat efficiently rerouting carbohydrates and free-fatty acids into lipid droplets, upregulating lipid coat protein gene Plin4, and relocating droplets nearer to the nucleus. Our results demonstrate the power of Entinostat to promote lipid synthesis and storage, allowing reduced systemic sugar levels and sequestration of toxic metabolites within protected protein-coated droplets, suggesting a potential therapeutic strategy for diseases such as diabetes and metabolic syndrome. PMID:27320682

  9. Minireview: The Link Between ERα Corepressors and Histone Deacetylases in Tamoxifen Resistance in Breast Cancer.

    PubMed

    Légaré, Stéphanie; Basik, Mark

    2016-09-01

    Approximately 70% of breast cancers express the estrogen receptor (ER)α and are treated with the ERα antagonist, tamoxifen. However, resistance to tamoxifen frequently develops in advanced breast cancer, in part due to a down-regulation of ERα corepressors. Nuclear receptor corepressors function by attenuating hormone responses and have been shown to potentiate tamoxifen action in various biological systems. Recent genomic data on breast cancers has revealed that genetic and/or genomic events target ERα corepressors in the majority of breast tumors, suggesting that the loss of nuclear receptor corepressor activity may represent an important mechanism that contributes to intrinsic and acquired tamoxifen resistance. Here, the biological functions of ERα corepressors are critically reviewed to elucidate their role in modifying endocrine sensitivity in breast cancer. We highlight a mechanism of gene repression common to corepressors previously shown to enhance the antitumorigenic effects of tamoxifen, which involves the recruitment of histone deacetylases (HDACs) to DNA. As an indicator of epigenetic disequilibrium, the loss of ERα corepressors may predispose cancer cells to the cytotoxic effects of HDAC inhibitors, a class of drug that has been shown to effectively reverse tamoxifen resistance in numerous studies. HDAC inhibition thus appears as a promising therapeutic approach that deserves to be further explored as an avenue to restore drug sensitivity in corepressor-deficient and tamoxifen-resistant breast cancers. PMID:27581354

  10. Histone Deacetylase Inhibitors Facilitate Dihydroartemisinin-Induced Apoptosis in Liver Cancer In Vitro and In Vivo

    PubMed Central

    Zhang, Chris Zhiyi; Pan, Yinghua; Cao, Yun; Lai, Paul B. S.; Liu, Lili; Chen, George Gong; Yun, Jingping

    2012-01-01

    Liver cancer ranks in prevalence and mortality among top five cancers worldwide. Accumulating interests have been focused in developing new strategies for liver cancer treatment. We have previously showed that dihydroartemisinin (DHA) exhibited antitumor activity towards liver cancer. In this study, we demonstrated that histone deacetylase inhibitors (HDACi) significantly augmented the antineoplastic effect of DHA via increasing apoptosis in vitro and in vivo. Inhibition of ERK phosphorylation contributed to DHA-induced apoptosis, due to the fact that inhibitor of ERK phosphorylation (PD98059) increased DHA-induced apoptosis. Compared with DHA alone, the combined treatment with DHA and HDACi reduced mitochondria membrane potential, released cytochrome c into cytoplasm, increased p53 and Bak, decreased Mcl-1 and p-ERK, activated caspase 3 and PARP, and induced apoptotic cells. Furthermore, we showed that HDACi pretreatment facilitated DHA-induced apoptosis. In Hep G2-xenograft carrying nude mice, the intraperitoneal injection of DHA and SAHA resulted in significant inhibition of xenograft tumors. Results of TUNEL and H&E staining showed more apoptosis induced by combined treatment. Immunohistochemistry data revealed the activation of PARP, and the decrease of Ki-67, p-ERK and Mcl-1. Taken together, our data suggest that the combination of HDACi and DHA offers an antitumor effect on liver cancer, and this combination treatment should be considered as a promising strategy for chemotherapy. PMID:22761917

  11. Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease.

    PubMed

    Cebotaru, Liudmila; Liu, Qiangni; Yanda, Murali K; Boinot, Clement; Outeda, Patricia; Huso, David L; Watnick, Terry; Guggino, William B; Cebotaru, Valeriu

    2016-07-01

    Abnormal proliferation of cyst-lining epithelium and increased intracystic fluid secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) are thought to contribute to cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Histone deacetylase 6 (HDAC6) expression and activity are increased in certain cancers, neurodegenerative diseases, and in Pkd1-mutant renal epithelial cells. Inhibition of HDAC6 activity with specific inhibitors slows cancer growth. Here we studied the effect of tubacin, a specific HDAC6 inhibitor, on cyst growth in polycystic kidney disease. Treatment with tubacin prevented cyst formation in MDCK cells, an in vitro model of cystogenesis. Cyclic AMP stimulates cell proliferation and activates intracystic CFTR-mediated chloride secretion in ADPKD. Treatment with tubacin downregulated cyclic AMP levels, inhibited cell proliferation, and inhibited cyclic AMP-activated CFTR chloride currents in MDCK cells. We also found that tubacin reduced cyst growth by inhibiting proliferation of cyst-lining epithelial cells, downregulated cyclic AMP levels, and improved renal function in a Pkd1-conditional mouse model of ADPKD. Thus, HDAC6 could play a role in cyst formation and could serve as a potential therapeutic target in ADPKD. PMID:27165822

  12. New histone deacetylase inhibitors improve cisplatin antitumor properties against thoracic cancer cells.

    PubMed

    Gueugnon, Fabien; Cartron, Pierre-François; Charrier, Cedric; Bertrand, Philippe; Fonteneau, Jean-François; Gregoire, Marc; Blanquart, Christophe

    2014-06-30

    Histone deacetylase inhibitors (HDACi) have shown promising antitumor effects on numerous cancer cells including malignant pleural mesothelioma (MPM) and lung adenocarcinoma (ADCA) cells. However, clinical trials using these compounds alone have shown limited efficacy against solid tumors. Therefore, new molecules are being developed and combinations with classical chemotherapeutic drugs are being tested. Here, we have evaluated on three MPM and three lung ADCA cell lines the antitumor potential of four new HDACi compounds, either alone or in combination with cisplatin. These effects were compared with those of vorinostat, an HDACi approved for cancer treatments. First, we characterized the HDAC mRNA expression profiles of tumor cells and showed an increase of the classI/classII HDAC ratio. We then treated cancer cells with these new HDACi and observed a cell-death induction and an increase of HDACi target genes and proteins expression. This was particularly evident for NODH compound (pan-HDACi) which had similar effects at nanomolar concentrations as micromolar concentrations of vorinostat. Interestingly, we observed that the HDACi/cisplatin combination strongly increased cell-death and limited resistance-phenotype emergence as compared with results obtained when the drugs were used alone. These results could be exploited to develop MPM and lung ADCA treatments combining chemotherapeutic approaches. PMID:24980825

  13. New histone deacetylase inhibitors improve cisplatin antitumor properties against thoracic cancer cells

    PubMed Central

    Gueugnon, Fabien; Cartron, Pierre-François; Charrier, Cedric; Bertrand, Philippe; Fonteneau, Jean-François; Gregoire, Marc; Blanquart, Christophe

    2014-01-01

    Histone deacetylase inhibitors (HDACi) have shown promising antitumor effects on numerous cancer cells including malignant pleural mesothelioma (MPM) and lung adenocarcinoma (ADCA) cells. However, clinical trials using these compounds alone have shown limited efficacy against solid tumors. Therefore, new molecules are being developed and combinations with classical chemotherapeutic drugs are being tested. Here, we have evaluated on three MPM and three lung ADCA cell lines the antitumor potential of four new HDACi compounds, either alone or in combination with cisplatin. These effects were compared with those of vorinostat, an HDACi approved for cancer treatments. First, we characterized the HDAC mRNA expression profiles of tumor cells and showed an increase of the classI/classII HDAC ratio. We then treated cancer cells with these new HDACi and observed a cell-death induction and an increase of HDACi target genes and proteins expression. This was particularly evident for NODH compound (pan-HDACi) which had similar effects at nanomolar concentrations as micromolar concentrations of vorinostat. Interestingly, we observed that the HDACi/cisplatin combination strongly increased cell-death and limited resistance-phenotype emergence as compared with results obtained when the drugs were used alone. These results could be exploited to develop MPM and lung ADCA treatments combining chemotherapeutic approaches. PMID:24980825

  14. Probing the structure-activity relationship of endogenous histone deacetylase complexes with immobilized peptide-inhibitors.

    PubMed

    Sindlinger, Julia; Bierlmeier, Jan; Geiger, Lydia-Christina; Kramer, Katharina; Finkemeier, Iris; Schwarzer, Dirk

    2016-05-01

    Histone deacetylases (HDACs) are key regulators of numerous cellular proteins by removing acetylation marks from modified lysine residues. Peptide-based HDAC probes containing α-aminosuberic acid ω-hydroxamate have been established as useful tools for investigating substrate selectivity and composition of endogenous HDAC complexes in cellular lysates. Here we report a structure-activity study of potential HDAC-probes containing derivatives of the hydroxamate moieties. While most of these probes did not recruit significant amounts of endogenous HDACs from cellular lysates, peptides containing Nε-acetyl-Nε-hydroxy-L-lysine served as HDAC probe. The recruitment efficiency varied between HDACs and was generally lower than that of α-aminosuberic acid ω-hydroxamate probes, but showed a similar global interaction profile. These findings indicate that Nε-acetyl-Nε-hydroxy-L-lysine might be a useful tool for investigations on HDAC complexes and the development of HDAC inhibitors. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:27071932

  15. Class IIa Histone Deacetylases are Hormone-activated regulators of FOXO and Mammalian Glucose Homeostasis

    PubMed Central

    Mihaylova, Maria M.; Vasquez, Debbie S.; Ravnskjaer, Kim; Denechaud, Pierre-Damien; Yu, Ruth T.; Alvarez, Jacqueline G.; Downes, Michael; Evans, Ronald M.; Montminy, Marc; Shaw, Reuben J.

    2011-01-01

    SUMMARY Class IIa histone deacetylases (HDACs) are signal-dependent modulators of transcription with established roles in muscle differentiation and neuronal survival. We show here that in liver, Class IIa HDACs (HDAC4, 5, and 7) are phosphorylated and excluded from the nucleus by AMPK family kinases. In response to the fasting hormone glucagon, Class IIa HDACs are rapidly dephosphorylated and translocated to the nucleus where they associate with the promoters of gluconeogenic enzymes such as G6Pase. In turn, HDAC4/5 recruit HDAC3, which results in the acute transcriptional induction of these genes via deacetylation and activation of Foxo family transcription factors. Loss of Class IIa HDACs in murine liver results in inhibition of FOXO target genes and lowers blood glucose, resulting in increased glycogen storage. Finally, suppression of Class IIa HDACs in mouse models of Type 2 Diabetes ameliorates hyperglycemia, suggesting that inhibitors of Class I/II HDACs may be potential therapeutics for metabolic syndrome. PMID:21565617

  16. The histone deacetylase inhibiting drug Entinostat induces lipid accumulation in differentiated HepaRG cells

    NASA Astrophysics Data System (ADS)

    Nunn, Abigail D. G.; Scopigno, Tullio; Pediconi, Natalia; Levrero, Massimo; Hagman, Henning; Kiskis, Juris; Enejder, Annika

    2016-06-01

    Dietary overload of toxic, free metabolic intermediates leads to disrupted insulin signalling and fatty liver disease. However, it was recently reported that this pathway might not be universal: depletion of histone deacetylase (HDAC) enhances insulin sensitivity alongside hepatic lipid accumulation in mice, but the mechanistic role of microscopic lipid structure in this effect remains unclear. Here we study the effect of Entinostat, a synthetic HDAC inhibitor undergoing clinical trials, on hepatic lipid metabolism in the paradigmatic HepaRG liver cell line. Specifically, we statistically quantify lipid droplet morphology at single cell level utilizing label-free microscopy, coherent anti-Stokes Raman scattering, supported by gene expression. We observe Entinostat efficiently rerouting carbohydrates and free-fatty acids into lipid droplets, upregulating lipid coat protein gene Plin4, and relocating droplets nearer to the nucleus. Our results demonstrate the power of Entinostat to promote lipid synthesis and storage, allowing reduced systemic sugar levels and sequestration of toxic metabolites within protected protein-coated droplets, suggesting a potential therapeutic strategy for diseases such as diabetes and metabolic syndrome.

  17. The histone deacetylase inhibiting drug Entinostat induces lipid accumulation in differentiated HepaRG cells

    PubMed Central

    Nunn, Abigail D. G.; Scopigno, Tullio; Pediconi, Natalia; Levrero, Massimo; Hagman, Henning; Kiskis, Juris; Enejder, Annika

    2016-01-01

    Dietary overload of toxic, free metabolic intermediates leads to disrupted insulin signalling and fatty liver disease. However, it was recently reported that this pathway might not be universal: depletion of histone deacetylase (HDAC) enhances insulin sensitivity alongside hepatic lipid accumulation in mice, but the mechanistic role of microscopic lipid structure in this effect remains unclear. Here we study the effect of Entinostat, a synthetic HDAC inhibitor undergoing clinical trials, on hepatic lipid metabolism in the paradigmatic HepaRG liver cell line. Specifically, we statistically quantify lipid droplet morphology at single cell level utilizing label-free microscopy, coherent anti-Stokes Raman scattering, supported by gene expression. We observe Entinostat efficiently rerouting carbohydrates and free-fatty acids into lipid droplets, upregulating lipid coat protein gene Plin4, and relocating droplets nearer to the nucleus. Our results demonstrate the power of Entinostat to promote lipid synthesis and storage, allowing reduced systemic sugar levels and sequestration of toxic metabolites within protected protein-coated droplets, suggesting a potential therapeutic strategy for diseases such as diabetes and metabolic syndrome. PMID:27320682

  18. The histone deacetylase inhibitor Entinostat enhances polymer-mediated transgene expression in cancer cell lines.

    PubMed

    Elmer, Jacob J; Christensen, Matthew D; Barua, Sutapa; Lehrman, Jennifer; Haynes, Karmella A; Rege, Kaushal

    2016-06-01

    Eukaryotic cells maintain an immense amount of genetic information by tightly wrapping their DNA around positively charged histones. While this strategy allows human cells to maintain more than 25,000 genes, histone binding can also block gene expression. Consequently, cells express histone acetyl transferases (HATs) to acetylate histone lysines and release DNA for transcription. Conversely, histone deacetylases (HDACs) are employed for restoring the positive charge on the histones, thereby silencing gene expression by increasing histone-DNA binding. It has previously been shown that histones bind and silence viral DNA, while hyperacetylation of histones via HDAC inhibition restores viral gene expression. In this study, we demonstrate that treatment with Entinostat, an HDAC inhibitor, enhances transgene (luciferase) expression by up to 25-fold in human prostate and murine bladder cancer cell lines when used with cationic polymers for plasmid DNA delivery. Entinostat treatment altered cell cycle progression, resulting in a significant increase in the fraction of cells present in the G0/G1 phase at low micromolar concentrations. While this moderate G0/G1 arrest disappeared at higher concentrations, a modest increase in the fraction of apoptotic cells and a decrease in cell proliferation were observed, consistent with the known anticancer effects of the drug. DNase accessibility studies revealed no significant change in plasmid transcriptional availability with Entinostat treatment. However, quantitative PCR studies indicated that Entinostat treatment, at the optimal dose for enhancing transgene expression, led to an increase in the amount of plasmid present in the nucleus in two cancer cell lines. Taken together, our results show that Entinostat enhances polymer- mediated transgene expression and can be useful in applications related to transient protein expression in mammalian cells. Biotechnol. Bioeng. 2016;113: 1345-1356. © 2015 Wiley Periodicals, Inc. PMID

  19. Boric acid inhibits embryonic histone deacetylases: A suggested mechanism to explain boric acid-related teratogenicity

    SciTech Connect

    Di Renzo, Francesca; Cappelletti, Graziella; Broccia, Maria L.; Giavini, Erminio; Menegola, Elena . E-mail: elena.menegola@unimi.it

    2007-04-15

    Histone deacetylases (HDAC) control gene expression by changing histonic as well as non histonic protein conformation. HDAC inhibitors (HDACi) are considered to be among the most promising drugs for epigenetic treatment for cancer. Recently a strict relationship between histone hyperacetylation in specific tissues of mouse embryos exposed to two HDACi (valproic acid and trichostatin A) and specific axial skeleton malformations has been demonstrated. The aim of this study is to verify if boric acid (BA), that induces in rodents malformations similar to those valproic acid and trichostatin A-related, acts through similar mechanisms: HDAC inhibition and histone hyperacetylation. Pregnant mice were treated intraperitoneally with a teratogenic dose of BA (1000 mg/kg, day 8 of gestation). Western blot analysis and immunostaining were performed with anti hyperacetylated histone 4 (H4) antibody on embryos explanted 1, 3 or 4 h after treatment and revealed H4 hyperacetylation at the level of somites. HDAC enzyme assay was performed on embryonic nuclear extracts. A significant HDAC inhibition activity (compatible with a mixed type partial inhibition mechanism) was evident with BA. Kinetic analyses indicate that BA modifies substrate affinity by a factor {alpha} = 0.51 and maximum velocity by a factor {beta} = 0.70. This work provides the first evidence for HDAC inhibition by BA and suggests such a molecular mechanism for the induction of BA-related malformations.

  20. Class I Histone Deacetylase Thd1p Promotes Global Chromatin Condensation in Tetrahymena thermophila▿

    PubMed Central

    Parker, Kathryn; Maxson, Julia; Mooney, Alissa; Wiley, Emily A.

    2007-01-01

    Class I histone deacetylases (HDACs) regulate DNA-templated processes such as transcription. They act both at specific loci and more generally across global chromatin, contributing to acetylation patterns that may underlie large-scale chromatin dynamics. Although hypoacetylation is correlated with highly condensed chromatin, little is known about the contribution of individual HDACs to chromatin condensation mechanisms. Using the ciliated protozoan Tetrahymena thermophila, we investigated the role of a specific class I HDAC, Τhd1p, in the reversible condensation of global chromatin. In this system, the normal physiological response to cell starvation includes the widespread condensation of the macronuclear chromatin and general repression of gene transcription. We show that the chromatin in Thd1p-deficient cells failed to condense during starvation. The condensation failure correlated with aberrant hyperphosphorylation of histone H1 and the overexpression of CDC2, encoding the major histone H1 kinase. Changes in the rate of acetate turnover on core histones and in the distribution of acetylated lysines 9 and 23/27 on histone H3 isoforms that were found to correlate with normal chromatin condensation were absent from Thd1p mutant cells. These results point to a role for a class I HDAC in the formation of reversible higher-order chromatin structures and global genome compaction through mechanisms involving the regulation of H1 phosphorylation and core histone acetylation/deacetylation kinetics. PMID:17715364

  1. Lifespan extension and elevated hsp gene expression in Drosophila caused by histone deacetylase inhibitors.

    PubMed

    Zhao, Yanmei; Sun, Hui; Lu, Jun; Li, Xiaoxue; Chen, Xia; Tao, Dan; Huang, Weifeng; Huang, Baiqu

    2005-02-01

    The heat shock proteins (Hsps) play a positive role in lifespan determination, and histone acetylation has been shown to be involved in transcription of hsp genes in Drosophila. To further determine if hsp22 and hsp70 expression is correlated with lifespan, and if histone acetylation participates in this process, RNA levels for hsp22 and hsp70 were analyzed throughout the lifespan in the long-lived and short-lived iso-female lines. The results showed that hsp22 and hsp70 RNA levels were higher in long-lived line than in short-lived line and that the long-lived flies responded more rapidly to heat but were more tolerant to high temperature. Moreover, we investigated the influences of histone acetylation modification on longevity and on hsp gene expression by using histone deacetylase (HDAC) inhibitors TSA and BuA. The results demonstrated that both inhibitors were able to extend the lifespan and promote hsp22 and hsp70 expression. However, the optimal concentrations of these inhibitors, and probably the mechanisms of their actions, vary with the genetic background. In addition, we showed that HDAC inhibitors caused the hyperacetylation of core histone H3, implicating the involvement of chromatin modulation in hsp gene transcription. These data suggested a close correlation among histone acetylation, hsp gene expression and longevity in D. melanogaster. PMID:15695762

  2. Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development

    PubMed Central

    Hagelkruys, Astrid; Mattes, Katharina; Moos, Verena; Rennmayr, Magdalena; Ringbauer, Manuela; Sawicka, Anna

    2015-01-01

    The class I histone deacetylases (HDACs) HDAC1 and HDAC2 play partially redundant roles in the regulation of gene expression and mouse development. As part of multisubunit corepressor complexes, these two deacetylases exhibit both enzymatic and nonenzymatic functions. To examine the impact of the catalytic activities of HDAC1 and HDAC2, we generated knock-in mice expressing catalytically inactive isoforms, which are still incorporated into the HDAC1/HDAC2 corepressor complexes. Surprisingly, heterozygous mice expressing catalytically inactive HDAC2 die within a few hours after birth, while heterozygous HDAC1 mutant mice are indistinguishable from wild-type littermates. Heterozygous HDAC2 mutant mice show an unaltered composition but reduced associated deacetylase activity of corepressor complexes and exhibit a more severe phenotype than HDAC2-null mice. They display changes in brain architecture accompanied by premature expression of the key regulator protein kinase C delta. Our study reveals a dominant negative effect of catalytically inactive HDAC2 on specific corepressor complexes resulting in histone hyperacetylation, transcriptional derepression, and, ultimately, perinatal lethality. PMID:26598605

  3. Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile.

    PubMed

    Boskovic, Zarko V; Kemp, Melissa M; Freedy, Allyson M; Viswanathan, Vasanthi S; Pop, Marius S; Fuller, Jason H; Martinez, Nicole M; Figueroa Lazú, Samuel O; Hong, Jiyoung A; Lewis, Timothy A; Calarese, Daniel; Love, James D; Vetere, Amedeo; Almo, Steven C; Schreiber, Stuart L; Koehler, Angela N

    2016-07-15

    Unbiased binding assays involving small-molecule microarrays were used to identify compounds that display unique patterns of selectivity among members of the zinc-dependent histone deacetylase family of enzymes. A novel, hydroxyquinoline-containing compound, BRD4354, was shown to preferentially inhibit activity of HDAC5 and HDAC9 in vitro. Inhibition of deacetylase activity appears to be time-dependent and reversible. Mechanistic studies suggest that the compound undergoes zinc-catalyzed decomposition to an ortho-quinone methide, which covalently modifies nucleophilic cysteines within the proteins. The covalent nature of the compound-enzyme interaction has been demonstrated in experiments with biotinylated probe compound and with electrospray ionization-mass spectrometry. PMID:27064299

  4. Inhibition of maize histone deacetylases by HC toxin, the host-selective toxin of Cochliobolus carbonum.

    PubMed Central

    Brosch, G; Ransom, R; Lechner, T; Walton, J D; Loidl, P

    1995-01-01

    HC toxin, the host-selective toxin of the maize pathogen Cochliobolus carbonum, inhibited maize histone deacetylase (HD) at 2 microM. Chlamydocin, a related cyclic tetrapeptide, also inhibited HD activity. The toxins did not affect histone acetyltransferases. After partial purification of histone deacetylases HD1-A, HD1-B, and HD2 from germinating maize embryos, we demonstrated that the different enzymes were similarly inhibited by the toxins. Inhibitory activities were reversibly eliminated by treating toxins with 2-mercaptoethanol, presumably by modifying the carbonyl group of the epoxide-containing amino acid Aeo (2-amino-9,10-epoxy-8-oxodecanoic acid). Kinetic studies revealed that inhibition of HD was of the uncompetitive type and reversible. HC toxin, in which the epoxide group had been hydrolyzed, completely lost its inhibitory activity; when the carbonyl group of Aeo had been reduced to the corresponding alcohol, the modified toxin was less active than native toxin. In vivo treatment of embryos with HC toxin caused the accumulation of highly acetylated histone H4 subspecies and elevated acetate incorporation into H4 in susceptible-genotype embryos but not in the resistant genotype. HDs from chicken and the myxomycete Physarum polycephalum were also inhibited, indicating that the host selectivity of HC toxin is not determined by its inhibitory effect on HD. Consistent with these results, we propose a model in which HC toxin promotes the establishment of pathogenic compatibility between C. carbonum and maize by interfering with reversible histone acetylation, which is implicated in the control of fundamental cellular processes, such as chromatin structure, cell cycle progression, and gene expression. PMID:8535144

  5. Isolation and characterization of an osmotic stress and ABA induced histone deacetylase in Arachis hygogaea

    PubMed Central

    Su, Liang-Chen; Deng, Bin; Liu, Shuai; Li, Li-Mei; Hu, Bo; Zhong, Yu-Ting; Li, Ling

    2015-01-01

    Histone acetylation, which together with histone methylation regulates gene activity in response to stress, is an important epigenetic modification. There is an increasing research focus on histone acetylation in crops, but there is no information to date in peanut (Arachis hypogaea). We showed that osmotic stress and ABA affect the acetylation of histone H3 loci in peanut seedlings by immunoblotting experiments. Using RNA-seq data for peanut, we found a RPD3/HDA1-like superfamily histone deacetylase (HDAC), termed AhHDA1, whose gene is up-regulated by PEG-induced water limitation and ABA signaling. We isolated and characterized AhHDA1 from A. hypogaea, showing that AhHDA1 is very similar to an Arabidopsis HDAC (AtHDA6) and, in recombinant form, possesses HDAC activity. To understand whether and how osmotic stress and ABA mediate the peanut stress response by epigenetics, the expression of AhHDA1 and stress-responsive genes following treatment with PEG, ABA, and the specific HDAC inhibitor trichostatin A (TSA) were analyzed. AhHDA1 transcript levels were enhanced by all three treatments, as was expression of peanut transcription factor genes, indicating that AhHDA1 might be involved in the epigenetic regulation of stress resistance genes that comprise the responses to osmotic stress and ABA. PMID:26217363

  6. Glucocorticoid Receptor Recruitment of Histone Deacetylase 2 Inhibits Interleukin-1β-Induced Histone H4 Acetylation on Lysines 8 and 12

    PubMed Central

    Ito, Kazuhiro; Barnes, Peter J.; Adcock, Ian M.

    2000-01-01

    We have investigated the ability of dexamethasone to regulate interleukin-1β (IL-1β)-induced gene expression, histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity. Low concentrations of dexamethasone (10−10 M) repress IL-1β-stimulated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression and fail to stimulate secretory leukocyte proteinase inhibitor expression. Dexamethasone (10−7 M) and IL-1β (1 ng/ml) both stimulated HAT activity but showed a different pattern of histone H4 acetylation. Dexamethasone targeted lysines K5 and K16, whereas IL-1β targeted K8 and K12. Low concentrations of dexamethasone (10−10 M), which do not transactivate, repressed IL-1β-stimulated K8 and K12 acetylation. Using chromatin immunoprecipitation assays, we show that dexamethasone inhibits IL-1β-enhanced acetylated K8-associated GM-CSF promoter enrichment in a concentration-dependent manner. Neither IL-1β nor dexamethasone elicited any GM-CSF promoter association at acetylated K5 residues. Furthermore, we show that GR acts both as a direct inhibitor of CREB binding protein (CBP)-associated HAT activity and also by recruiting HDAC2 to the p65-CBP HAT complex. This action does not involve de novo synthesis of HDAC protein or altered expression of CBP or p300/CBP-associated factor. This mechanism for glucocorticoid repression is novel and establishes that inhibition of histone acetylation is an additional level of control of inflammatory gene expression. This further suggests that pharmacological manipulation of of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases. PMID:10958685

  7. Histone Deacetylases in Herpesvirus Replication and Virus-Stimulated Host Defense

    PubMed Central

    Guise, Amanda J.; Budayeva, Hanna G.; Diner, Benjamin A.; Cristea, Ileana M.

    2013-01-01

    Emerging evidence highlights a critical role for protein acetylation during herpesvirus infection. As prominent modulators of protein acetylation, histone deacetylases (HDACs) are essential transcriptional and epigenetic regulators. Not surprisingly, viruses have evolved a wide array of mechanisms to subvert HDAC functions. Here, we review the mechanisms underlying HDAC regulation during herpesvirus infection. We next discuss the roles of acetylation in host defense against herpesvirus infection. Finally, we provide a perspective on the contribution of current mass spectrometry-based “omic” technologies to infectious disease research, offering a systems biology view of infection. PMID:23807710

  8. 1,3,4-Oxadiazole-containing histone deacetylase inhibitors: anticancer activities in cancer cells.

    PubMed

    Valente, Sergio; Trisciuoglio, Daniela; De Luca, Teresa; Nebbioso, Angela; Labella, Donatella; Lenoci, Alessia; Bigogno, Chiara; Dondio, Giulio; Miceli, Marco; Brosch, Gerald; Del Bufalo, Donatella; Altucci, Lucia; Mai, Antonello

    2014-07-24

    We describe 1,3,4-oxadiazole-containing hydroxamates (2) and 2-aminoanilides (3) as histone deacetylase inhibitors. Among them, 2t, 2x, and 3i were the most potent and selective against HDAC1. In U937 leukemia cells, 2t was more potent than SAHA in inducing apoptosis, and 3i displayed cell differentiation with a potency similar to MS-275. In several acute myeloid leukemia (AML) cell lines, as well as in U937 cells in combination with doxorubicin, 3i showed higher antiproliferative effects than SAHA. PMID:24972008

  9. Histone deacetylase inhibition: an important mechanism in the treatment of lymphoma.

    PubMed

    Guo, Shan-Qi; Zhang, Yi-Zhuo

    2012-06-01

    Lymphomas encompass a group of malignancies that originate in the lymph nodes or other lymphoid tissues. Epigenetic modification, especially by histone deacetylase (HDACs), plays a key role during the occurrence and development of lymphomas. Consequently, HDAC inhibitors (HDACIs), a class of gene expression-modulating drugs, have emerged as promising mechanism-based agents for the treatment of lymphomas. This review presents the rationale of HDAC inhibition, describes the epigenetic-based mechanisms of action of HDACIs, discusses their clinical efficiency, and summarizes the current and future developments in this field. PMID:23691460

  10. Histone deacetylase inhibitors increase glucocerebrosidase activity in Gaucher disease by modulation of molecular chaperones

    PubMed Central

    Yang, Chunzhang; Rahimpour, Shervin; Lu, Jie; Pacak, Karel; Ikejiri, Barbara; Brady, Roscoe O.; Zhuang, Zhengping

    2013-01-01

    Gaucher disease is caused by mutations of the GBA gene that encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA mutations often result in protein misfolding and premature degradation, but usually exert less effect on catalytic activity. In this study, we identified the molecular mechanism by which histone deacetylase inhibitors increase the quantity and activity of GCase. Specifically, these inhibitors limit the deacetylation of heat shock protein 90, resulting in less recognition of the mutant peptide and GCase degradation. These findings provide insight into a possible therapeutic strategy for Gaucher disease and other genetic disorders by modifying molecular chaperone and protein degradation pathways. PMID:23277556

  11. The inhibition of histone deacetylase 8 suppresses proliferation and inhibits apoptosis in gastric adenocarcinoma.

    PubMed

    Song, Shiyuan; Wang, Ying; Xu, Po; Yang, Ruina; Ma, Zhikun; Liang, Shuo; Zhang, Guangping

    2015-11-01

    Histone deacetylase 8 (HDAC8), a unique member of class I HDACs, shows remarkable correlation with advanced disease stage. The depletion of HDAC8 leads to inhibition of proliferation, apoptosis and cell cycle arrest in multiple malignant tumors. However, little is known about the contribution of HDAC8 to the tumorigenesis of gastric cancer (GC). The present study investigated expression of HDAC8 in GC cell lines and tissues, and the roles of HDAC8 inhibition in the proliferation, cell cycle and apoptosis of gastric cancer cells and explored the potential mechanisms. In the present study, quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry were used to examine the mRNA and protein expression of HDAC8 in GC cell lines and tissues. Then, the correlation between the clinicopathological parameters and the expression of HDAC8 was assessed. Finally, siRNA transfection and HDAC8 plasmid was performed to explore the functions of HDAC8 in GC progression in vitro. We found that the expression of HDAC8 was significantly upregulated both in GC cell lines and tumor tissues compared to human normal gastric epithelial cell, GES-1 and matched non-tumor tissues. Furthermore, depletion of HDAC8 remarkably inhibited GC cell proliferation, increased the apoptosis rate and G0/G1 phase percentage in vitro. Western blotting showed that the expression of protein promoting apoptosis such as, Bmf, activated caspase-3, caspase-6 were elevated following HDAC8 depletion. Our data exhibited an important role of HDAC8 in promoting gastric cancer tumorigenesis and identify this HDAC8 as a potential therapeutic target for the treatment of gastric cancer. PMID:26412386

  12. Design and development of histone deacetylase (HDAC) chemical probes for cell-based profiling.

    PubMed

    Albrow, Victoria E; Grimley, Rachel L; Clulow, James; Rose, Colin R; Sun, Jianmin; Warmus, Joseph S; Tate, Edward W; Jones, Lyn H; Storer, R Ian

    2016-05-24

    Histone deacetylases (HDACs) contribute to regulation of gene expression by mediating higher-order chromatin structures. They assemble into large multiprotein complexes that regulate activity and specificity. We report the development of small molecule probes with class IIa and pan-HDAC activity that contain photoreactive crosslinking groups and either a biotin reporter, or a terminal alkyne handle for subsequent bioorthogonal ligation. The probes retained inhibitory activity against recombinant HDAC proteins and caused an accumulation of acetylated histone and tubulin following cell treatment. The versatility of the probes has been demonstrated by their ability to photoaffinity modify HDAC targets in vitro. An affinity enrichment probe was used in conjunction with mass spectrometry proteomics to isolate HDACs and their interacting proteins in a native proteome. The performance of the probes in recombinant versus cell-based systems highlights issues for the development of chemoproteomic technologies targeting class IIa HDACs in particular. PMID:27021930

  13. Murine hematopoietic stem cell dormancy controlled by induction of a novel short form of PSF1 by histone deacetylase inhibitors

    SciTech Connect

    Han, Yinglu; Gong, Zhi-Yuan; Takakura, Nobuyuki

    2015-06-10

    Hematopoietic stem cells (HSCs) can survive long-term in a state of dormancy. Little is known about how histone deacetylase inhibitors (HDACi) affect HSC kinetics. Here, we use trichostatin A (TSA), a histone deacetylase inhibitor, to enforce histone acetylation and show that this suppresses cell cycle entry by dormant HSCs. Previously, we found that haploinsufficiency of PSF1, a DNA replication factor, led to attenuation of the bone marrow (BM) HSC pool size and lack of acute proliferation after 5-FU ablation. Because PSF1 protein is present in CD34{sup +} transiently amplifying HSCs but not in CD34{sup −} long-term reconstituting-HSCs which are resting in a dormant state, we analyzed the relationship between dormancy and PSF1 expression, and how a histone deacetylase inhibitor affects this. We found that CD34{sup +} HSCs produce long functional PSF1 (PSF1a) but CD34{sup −} HSCs produce a shorter possibly non-functional PSF1 (PSF1b, c, dominantly PSF1c). Using PSF1a-overexpressing NIH-3T3 cells in which the endogenous PSF1 promoter is suppressed, we found that TSA treatment promotes production of the shorter form of PSF1 possibly by inducing recruitment of E2F family factors upstream of the PSF1 transcription start site. Our data document one mechanism by which histone deacetylase inhibitors affect the dormancy of HSCs by regulating the DNA replication factor PSF1. - Highlights: • Hematopoetic stem cell dormancy is controlled by histone deacetylation inhibitors. • Dormancy of HSCs is associated with a shorter form of non-functional PSF1. • Histone deacetylase inhibitors suppress PSF1 promoter activity.

  14. MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein

    PubMed Central

    Xia, Zhen-Biao; Anderson, Melanie; Diaz, Manuel O.; Zeleznik-Le, Nancy J.

    2003-01-01

    The MLL (mixed-lineage leukemia) gene is involved in many chromosomal translocations associated with acute myeloid and lymphoid leukemia. We previously identified a transcriptional repression domain in MLL, which contains a region with homology to DNA methyltransferase. In chromosomal translocations, the MLL repression domain is retained in the leukemogenic fusion protein and is required for transforming activity of MLL fusion proteins. We explored the mechanism of action of the MLL repression domain. Histone deacetylase 1 interacts with the MLL repression domain, partially mediating its activity; binding of Cyp33 to the adjacent MLL-PHD domain potentiates this binding. Because the MLL repression domain activity was only partially relieved with the histone deacetylase inhibitor trichostatin A, we explored other protein interactions with this domain. Polycomb group proteins HPC2 and BMI-1 and the corepressor C-terminal-binding protein also bind the MLL repression domain. Expression of exogenous BMI-1 potentiates MLL repression domain activity. Functional antagonism between Mll and Bmi-1 has been shown genetically in murine knockout models for Mll and Bmi-1. Our new data suggest a model whereby recruitment of BMI-1 to the MLL protein may be able to modulate its function. Furthermore, repression mediated by histone deacetylases and that mediated by polycomb group proteins may act either independently or together for MLL function in vivo. PMID:12829790

  15. Histone deacetylase HDA9 negatively regulates salt and drought stress responsiveness in Arabidopsis.

    PubMed

    Zheng, Yu; Ding, Yue; Sun, Xuan; Xie, Sisi; Wang, Dan; Liu, Xiaoyun; Su, Lufang; Wei, Wei; Pan, Lei; Zhou, Dao-Xiu

    2016-04-01

    Histone modification is an important epigenetic regulation in higher plants adapting to environment changes including salt and drought stresses. In this report, we show that the Arabidopsis RPD3-type histone deacetylase HDA9 is involved in modulating plant responses to salt and drought stresses in Arabidopsis. Loss-of-function mutants of the gene displayed phenotypes (such as seedling root growth and seed germination) insensitive to NaCl and polyethylene glycol (PEG) treatments. HDA9 mutation led to up-regulation of many genes, among which those involved in response to water deprivation stress (GO: 0009414) were enriched. These genes were much more induced in the mutants than wild-type plants when treated with PEG and NaCl. In addition, we found that in the mutants, salt and drought stresses led to much higher levels of histone H3K9 acetylation at promoters of 14 genes randomly selected from those that respond to water-deprivation stress than in wild-type plants. Our study suggested that HDA9 might be a novel chromatin protein that negatively regulates plant sensitivity to salt and drought stresses by regulating histone acetylation levels of a large number of stress-responsive genes in Arabidopsis. PMID:26733691

  16. Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory

    PubMed Central

    Hait, Nitai C; Wise, Laura E; Allegood, Jeremy C; O’Brien, Megan; Avni, Dorit; Reeves, Thomas M; Knapp, Pamela E; Lu, Junyan; Luo, Cheng; Miles, Michael F; Milstien, Sheldon; Lichtman, Aron H; Spiegel, Sarah

    2014-01-01

    FTY720 (fingolimod), an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. We show that FTY720 enters the nucleus, where it is phosphorylated by sphingosine kinase 2 (SphK2), and that nuclear FTY720-P binds and inhibits class I histone deacetylases (HDACs), enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in the brain, including the hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning, and rescues memory deficits independently of its immunosuppressive actions. Sphk2−/− mice have lower levels of hippocampal sphingosine-1-phosphate, an endogenous HDAC inhibitor, and reduced histone acetylation, and display deficits in spatial memory and impaired contextual fear extinction. Thus, sphingosine-1-phosphate and SphK2 play specific roles in memory functions and FTY720 may be a useful adjuvant therapy to facilitate extinction of aversive memories. PMID:24859201

  17. A Histone Deacetylase Adjusts Transcription Kinetics at Coding Sequences during Candida albicans Morphogenesis

    PubMed Central

    Hnisz, Denes; Bardet, Anaïs F.; Nobile, Clarissa J.; Petryshyn, Andriy; Glaser, Walter; Schöck, Ulrike; Stark, Alexander; Kuchler, Karl

    2012-01-01

    Despite their classical role as transcriptional repressors, several histone deacetylases, including the baker's yeast Set3/Hos2 complex (Set3C), facilitate gene expression. In the dimorphic human pathogen Candida albicans, the homologue of the Set3C inhibits the yeast-to-filament transition, but the precise molecular details of this function have remained elusive. Here, we use a combination of ChIP–Seq and RNA–Seq to show that the Set3C acts as a transcriptional co-factor of metabolic and morphogenesis-related genes in C. albicans. Binding of the Set3C correlates with gene expression during fungal morphogenesis; yet, surprisingly, deletion of SET3 leaves the steady-state expression level of most genes unchanged, both during exponential yeast-phase growth and during the yeast-filament transition. Fine temporal resolution of transcription in cells undergoing this transition revealed that the Set3C modulates transient expression changes of key morphogenesis-related genes. These include a transcription factor cluster comprising of NRG1, EFG1, BRG1, and TEC1, which form a regulatory circuit controlling hyphal differentiation. Set3C appears to restrict the factors by modulating their transcription kinetics, and the hyperfilamentous phenotype of SET3-deficient cells can be reverted by mutating the circuit factors. These results indicate that the chromatin status at coding regions represents a dynamic platform influencing transcription kinetics. Moreover, we suggest that transcription at the coding sequence can be transiently decoupled from potentially conflicting promoter information in dynamic environments. PMID:23236295

  18. Radiosensitizing Effect of a Phenylbutyrate-Derived Histone Deacetylase Inhibitor in Hepatocellular Carcinoma

    SciTech Connect

    Lu, Yen-Shen; Chou, Chia-Hung; Tzen, Kai-Yuan; Gao, Ming; Cheng, Ann-Lii; Kulp, Samuel K.; Cheng, Jason Chia-Hsien

    2012-06-01

    Purpose: Radiotherapy is integrated into the multimodal treatment of localized hepatocellular carcinoma (HCC) refractory to conventional treatment. Tumor control remains unsatisfactory and the sublethal effect associates with secondary spread. The use of an effective molecularly targeted agent in combination with radiotherapy is a potential therapeutic approach. Our aim was to assess the effect of combining a phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, AR-42, with radiotherapy in in vitro and in vivo models of human HCC. Methods and Materials: Human HCC cell lines (Huh-7 and PLC-5) were used to evaluate the in vitro synergism of combining AR-42 with irradiation. Flow cytometry analyzed the cell cycle changes, whereas Western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with AR-42 and/or radiotherapy for the in vivo response. Results: AR-42 significantly enhanced radiation-induced cell death by the inhibition of the DNA end-binding activity of Ku70, a highly versatile regulatory protein for DNA repair, telomere maintenance, and apoptosis. In ectopic xenografts of Huh-7 and PLC-5, pretreatment with AR-42 significantly enhanced the tumor-suppressive effect of radiotherapy by 48% and 66%, respectively. A similar combinatorial effect of AR-42 (10 and 25 mg/kg) and radiotherapy was observed in Huh-7 orthotopic model of tumor growth by 52% and 82%, respectively. This tumor suppression was associated with inhibition of intratumoral Ku70 activity as well as reductions in markers of HDAC activity and proliferation, and increased apoptosis. Conclusion: AR-42 is a potent, orally bioavailable inhibitor of HDAC with therapeutic value as a radiosensitizer of HCC.

  19. Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat.

    PubMed

    Sooraj, Dhanya; Xu, Dakang; Cain, Jason E; Gold, Daniel P; Williams, Bryan R G

    2016-07-01

    Improved treatment strategies are required for bladder cancer due to frequent recurrence of low-grade tumors and poor survival rate from high-grade tumors with current therapies. Histone deacetylase inhibitors (HDACi), approved as single agents for specific lymphomas, have shown promising preclinical results in solid tumors but could benefit from identification of biomarkers for response. Loss of activating transcription factor 3 (ATF3) expression is a feature of bladder tumor progression and correlates with poor survival. We investigated the utility of measuring ATF3 expression as a marker of response to the HDACi pracinostat in bladder cancer models. Pracinostat treatment of bladder cancer cell lines reactivated the expression of ATF3, correlating with significant alteration in proliferative, migratory, and anchorage-dependent growth capacities. Pracinostat also induced growth arrest at the G0-G1 cell-cycle phase, coincident with the activation of tumor suppressor genes. In mouse xenograft bladder cancer models, pracinostat treatment significantly reduced tumor volumes compared with controls, accompanied by reexpression of ATF3 in nonproliferating cells from early to late stage of therapy and in parallel induced antiangiogenesis and apoptosis. Importantly, cells in which ATF3 expression was depleted were less sensitive to pracinostat treatment in vitro, exhibiting significantly higher proliferative and migratory properties. In vivo, control xenograft tumors were significantly more responsive to treatment than ATF3 knockdown xenografts. Thus, reactivation of ATF3 is an important factor in determining sensitivity to pracinostat treatment, both in vitro and in vivo, and could serve as a potential biomarker of response and provide a rationale for therapeutic utility in HDACi-mediated treatments for bladder cancer. Mol Cancer Ther; 15(7); 1726-39. ©2016 AACR. PMID:27196751

  20. Computer-aided identification of new histone deacetylase 6 selective inhibitor with anti-sepsis activity.

    PubMed

    Yoo, Jakyung; Kim, So-Jin; Son, Dohyun; Seo, Heewon; Baek, Seung Yeop; Maeng, Cheol-Young; Lee, Changsik; Kim, In Su; Jung, Young Hoon; Lee, Sun-Mee; Park, Hyun-Ju

    2016-06-30

    Histone deacetylase (HDAC) inhibitors have been recognized as promising approaches to the treatment of various human diseases including cancer, inflammation, neurodegenerative diseases, and metabolic disorders. Several pan-HDAC inhibitors are currently approved only as anticancer drugs. Interestingly, SAHA (vorinostat), one of clinically available pan-HDAC inhibitors, shows an anti-inflammatory effect at concentrations lower than those required for inhibition of tumor cell growth. It was also reported that HDAC6 selective inhibitor tubastatin A has anti-inflammatory and anti-rheumatic effect. In our efforts to develop novel HDAC inhibitors, we rationally designed various HDAC inhibitors based on the structures of two hit compounds identified by virtual screening of chemical database. Among them, 9a ((E)-N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide) was identified as a HDAC6 selective inhibitor (IC50 values of 0.199 μM for HDAC6 versus 13.8 μM for HDAC1), and it did not show significant cytotoxicity against HeLa cells. In vivo biological evaluation of 9a was conducted on a lipopolysaccharide (LPS)-induced mouse model of sepsis. The compound 9a significantly improved 40% survival rate (P = 0.0483), and suppressed the LPS-induced increase of TNF-α and IL-6 mRNA expression in the liver of mice. Our study identified novel HDAC6 selective inhibitor 9a, which may serve as a potential lead for the development of anti-inflammatory or anti-sepsis agents. PMID:27060764

  1. Histone deacetylase inhibitors epigenetically promote reparative events in primary dental pulp cells

    SciTech Connect

    Duncan, Henry F.; Smith, Anthony J.; Fleming, Garry J.P.; Cooper, Paul R.

    2013-06-10

    Application of histone deacetylase inhibitors (HDACi) to cells epigenetically alters their chromatin structure and induces transcriptional and cellular reparative events. This study investigated the application of two HDACi, valproic acid (VPA) and trichostatin A (TSA) on the induction of repair-associated responses in primary dental pulp cell (DPC) cultures. Flow cytometry demonstrated that TSA (100 nM, 400 nM) significantly increased cell viability. Neither HDACi was cytotoxic, although cell growth analysis revealed significant anti-proliferative effects at higher concentrations for VPA (>0.5 mM) and TSA (>50 nM). While high-content-analysis demonstrated that HDACi did not significantly induce caspase-3 or p21 activity, p53-expression was increased by VPA (3 mM, 5 mM) at 48 h. HDACi-exposure induced mineralization per cell dose-dependently to a plateau level (VPA-0.125 mM and TSA-25 nM) with accompanying increases in mineralization/dentinogenic-associated gene expression at 5 days (DMP-1, BMP-2/-4, Nestin) and 10 days (DSPP, BMP-2/-4). Both HDACis, at a range of concentrations, significantly stimulated osteopontin and BMP-2 protein expression at 10 and 14 days further supporting the ability of HDACi to promote differentiation. HDACi exert different effects on primary compared with transformed DPCs and promote mineralization and differentiation events without cytotoxic effects. These novel data now highlight the potential in restorative dentistry for applying low concentrations of HDACi in vital pulp treatment. -- Highlights: • Valproic acid and trichostatin A promoted mineralization in primary pulp cells. • Cell viability, apoptosis, caspase-3, p21 unaltered; p53 increased by valproic acid. • Trichostatin A increased cell viability at 24 h at selected concentrations. • Altered cell toxicity and differentiation between primary and transformed cells. • HDACi-induced the differentiation marker proteins osteopontin and BMP-2.

  2. Oxidative and Nitrosative Stress and Histone Deacetylase-2 Activity in Exacerbations of COPD

    PubMed Central

    Footitt, Joseph; Mallia, Patrick; Durham, Andrew L.; Ho, W. Eugene; Trujillo-Torralbo, Maria-Belen; Telcian, Aurica G.; Del Rosario, Ajerico; Chang, Cheng; Peh, Hong-Yong; Kebadze, Tatiana; Aniscenko, Julia; Stanciu, Luminita; Essilfie-Quaye, Sarah; Ito, Kazuhiro; Barnes, Peter J.; Elkin, Sarah L.; Kon, Onn M.; Wong, W. S. Fred; Adcock, Ian M.; Johnston, Sebastian L.

    2016-01-01

    Background Respiratory virus infections are commonly associated with COPD exacerbations, but little is known about the mechanisms linking virus infection to exacerbations. Pathogenic mechanisms in stable COPD include oxidative and nitrosative stress and reduced activity of histone deacetylase-2 (HDAC2), but their roles in COPD exacerbations is unknown. We investigated oxidative and nitrosative stress (O&NS) and HDAC2 in COPD exacerbations using experimental rhinovirus infection. Methods Nine subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II), 10 smokers, and 11 nonsmokers were successfully infected with rhinovirus. Markers of O&NS-associated cellular damage, and inflammatory mediators and proteases were measured in sputum, and HDAC2 activity was measured in sputum and bronchoalveolar macrophages. In an in vitro model, monocyte-derived THP-1 cells were infected with rhinovirus and nitrosylation and activity of HDAC2 was measured. Results Rhinovirus infection induced significant increases in airways inflammation and markers of O&NS in subjects with COPD. O&NS markers correlated with virus load and inflammatory markers. Macrophage HDAC2 activity was reduced during exacerbation and correlated inversely with virus load, inflammatory markers, and nitrosative stress. Sputum macrophage HDAC2 activity pre-infection was inversely associated with sputum virus load and inflammatory markers during exacerbation. Rhinovirus infection of monocytes induced nitrosylation of HDAC2 and reduced HDAC2 activity; inhibition of O&NS inhibited rhinovirus-induced inflammatory cytokines. Conclusions O&NS, airways inflammation, and impaired HDAC2 may be important mechanisms of virus-induced COPD exacerbations. Therapies targeting these mechanisms offer potential new treatments for COPD exacerbations. PMID:25790167

  3. HLA ligandomics identifies histone deacetylase 1 as target for ovarian cancer immunotherapy

    PubMed Central

    Peper, Janet Kerstin; Bösmüller, Hans-Christian; Schuster, Heiko; Gückel, Brigitte; Hörzer, Helen; Roehle, Kevin; Schäfer, Richard; Wagner, Philipp; Rammensee, Hans-Georg; Stevanović, Stefan; Fend, Falko; Staebler, Annette

    2016-01-01

    abstract The recent approval of clincially effective immune checkpoint inhibitors illustrates the potential of cancer immunotherapy. A challenging task remains the identification of specific targets guiding immunotherapy. Facilitated by technical advances, the direct identification of physiologically relevant targets is enabled by analyzing the HLA ligandome of cancer cells. Since recent publications demonstrate the immunogenicity of ovarian cancer (OvCa), immunotherapies, including peptide-based cancer vaccines, represent a promising treatment approach. To identify vaccine peptides, we employed a combined strategy of HLA ligandomics in high-grade serous OvCa samples and immunogenicity analysis. Only few proteins were naturally presented as HLA ligands on all samples analyzed, including histone deacetylase (HDAC) 1 and 2. In vitro priming of CD8+ T cells demonstrated that two HDAC1/2-derived HLA ligands can induce T-cell responses, capable of killing HLA-matched tumor cells. High HDAC1 expression shown by immunohistochemistry in 136 high-grade serous OvCa patients associated with significantly reduced overall survival (OS), whereas patients with high numbers of CD3+ tumor-infiltrating lymphocytes (TILs) in the tumor epithelium and CD8+ TILs in the tumor stroma showed improved OS. However, correlating HDAC1 expression with TILs, high levels of TILs abrogated the impact of HDAC1 on OS. This study strengthens the role of HDAC1/2 as an important tumor antigen in OvCa, demonstrating its impact on OS in a large cohort of OvCa patients. We further identified two immunogenic HDAC1-derived peptides, which frequently induce multi-functional T-cell responses in many donors, suitable for future multi-peptide vaccine trials in OvCa patients.

  4. Biomarkers of Histone Deacetylase Inhibitor Activity in a Phase 1 Combined-Modality Study with Radiotherapy

    PubMed Central

    Ree, Anne Hansen; Saelen, Marie Grøn; Kalanxhi, Erta; Østensen, Ingrid H. G.; Schee, Kristina; Røe, Kathrine; Abrahamsen, Torveig Weum; Dueland, Svein; Flatmark, Kjersti

    2014-01-01

    Background Following the demonstration that histone deacetylase inhibitors enhanced experimental radiation-induced clonogenic suppression, the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study, combining fractionated radiotherapy with daily vorinostat for pelvic carcinoma, was designed to evaluate both clinical and novel biomarker endpoints, the latter relating to pharmacodynamic indicators of vorinostat action in clinical radiotherapy. Patients and Methods Potential biomarkers of vorinostat radiosensitizing action, not simultaneously manifesting molecular perturbations elicited by the radiation itself, were explored by gene expression array analysis of study patients' peripheral blood mononuclear cells (PBMC), sampled at baseline (T0) and on-treatment two and 24 hours (T2 and T24) after the patients had received vorinostat. Results This strategy revealed 1,600 array probes that were common for the comparisons T2 versus T0 and T24 versus T2 across all of the patients, and furthermore, that no significantly differential expression was observed between the T0 and T24 groups. Functional annotation analysis of the array data showed that a significant number of identified genes were implicated in gene regulation, the cell cycle, and chromatin biology. Gene expression was validated both in patients' PBMC and in vorinostat-treated human carcinoma xenograft models, and transient repression of MYC was consistently observed. Conclusion Within the design of the PRAVO study, all of the identified genes showed rapid and transient induction or repression and therefore, in principle, fulfilled the requirement of being pharmacodynamic biomarkers of vorinostat action in fractionated radiotherapy, possibly underscoring the role of MYC in this therapeutic setting. PMID:24587009

  5. Inhibition of Plasmodium falciparum proliferation in vitro by double-stranded RNA directed against malaria histone deacetylase

    SciTech Connect

    Sriwilaijaroen, N.; Boonma, S.; Attasart, P.; Pothikasikorn, J.; Panyim, S.; Noonpakdee, W.

    2009-04-03

    Acetylation and deacetylation of histones play important roles in transcription regulation, cell cycle progression and development events. The steady state status of histone acetylation is controlled by a dynamic equilibrium between competing histone acetylase and deacetylase (HDAC). We have used long PfHDAC-1 double-stranded (ds)RNA to interfere with its cognate mRNA expression and determined the effect on malaria parasite growth and development. Chloroquine- and pyrimethamine-resistant Plasmodium falciparum K1 strain was exposed to 1-25 {mu}g of dsRNA/ml of culture for 48 h and growth was determined by [{sup 3}H]-hypoxanthine incorporation and microscopic examination. Parasite culture treated with 10 {mu}g/ml pfHDAC-1 dsRNA exhibited 47% growth inhibition when compared with either untreated control or culture treated with an unrelated dsRNA. PfHDAC-1 dsRNA specifically blocked maturation of trophozoite to schizont stages and decreased PfHDAC-1 transcript 44% in treated trophozoites. These results indicate the potential of HDAC-1 as a target for development of novel antimalarials.

  6. Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells.

    PubMed

    Fiskus, Warren; Sharma, Sunil; Qi, Jun; Valenta, John A; Schaub, Leasha J; Shah, Bhavin; Peth, Karissa; Portier, Bryce P; Rodriguez, Melissa; Devaraj, Santhana G T; Zhan, Ming; Sheng, Jianting; Iyer, Swaminathan P; Bradner, James E; Bhalla, Kapil N

    2014-05-01

    The bromodomain and extra-terminal (BET) protein family members, including BRD4, bind to acetylated lysines on histones and regulate the expression of important oncogenes, for example, c-MYC and BCL2. Here, we demonstrate the sensitizing effects of the histone hyperacetylation-inducing pan-histone deacetylase (HDAC) inhibitor panobinostat on human acute myelogenous leukemia (AML) blast progenitor cells (BPC) to the BET protein antagonist JQ1. Treatment with JQ1, but not its inactive enantiomer (R-JQ1), was highly lethal against AML BPCs expressing mutant NPM1c+ with or without coexpression of FLT3-ITD or AML expressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of c-MYC and BCL2 and reduced their levels in the AML cells. Cotreatment with JQ1 and the HDAC inhibitor panobinostat synergistically induced apoptosis of the AML BPCs, but not of normal CD34(+) hematopoietic progenitor cells. This was associated with greater attenuation of c-MYC and BCL2, while increasing p21, BIM, and cleaved PARP levels in the AML BPCs. Cotreatment with JQ1 and panobinostat significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (P < 0.01). These findings highlight cotreatment with a BRD4 antagonist and an HDAC inhibitor as a potentially efficacious therapy of AML. PMID:24435446

  7. Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and behavioral abnormalities: Modulation of histone deacetylase activity.

    PubMed

    Sharma, Sorabh; Taliyan, Rajeev; Singh, Sumel

    2015-09-15

    Parkinson's disease (PD) is the second most common neurodegenerative disorder. Recent studies have investigated the involvement of epigenetic modifications in PD. Histone deacetylase (HDAC) inhibitors have been reported to be beneficial in cognitive and motor deficit states. The present study was designed to investigate the effect of sodium butyrate, a HDAC inhibitor in 6-hydroxydopamine (6-OHDA) - induced experimental PD like symptoms in rats. To produce motor deficit, 6-OHDA was administered unilaterally in the right medial forebrain bundle. Three weeks after 6-OHDA administration, the rats were challenged with apomorphine. Following this, the animals were treated with sodium butyrate (150 and 300 mg/kg i.p.) once daily for 14 days. Movement abnormalities were assessed by battery of behavioral tests. Biochemically, oxidative stress markers, neuroinflammation and dopamine were measured in striatal brain homogenate. Further, to explore the molecular mechanism(s), we measured the level of global H3 histone acetylation and brain derived neurotrophic factor (BDNF). 6-OHDA administration results in significant motor deficit along with reduction in striatal dopamine level. 6-OHDA treated rats showed elevated oxidative stress and neuroinflammatory markers. Treatment with sodium butyrate results in significant attenuation of motor deficits and increased striatal dopamine level. Moreover, sodium butyrate treatment attenuated the oxidative stress and neuroinflammatory markers. These effects occur concurrently with increased global H3 histone acetylation and BDNF levels. Thus, the observed results of the present study are indicative for the therapeutic potential of HDAC inhibitors in PD. PMID:26048426

  8. Reassessing the Effects of Histone Deacetylase Inhibitors on Hippocampal Memory and Cognitive Aging

    PubMed Central

    Castellano, James F.; Fletcher, Bonnie R.; Patzke, Holger; Long, Jeffrey M.; Sewal, Angila; Kim, David H.; Kelley-Bell, Bennett; Rapp, Peter R.

    2014-01-01

    Converging results link histone acetylation dynamics to hippocampus-dependent memory, including evidence that histone deacetylase inhibitor (HDACi) administration enhances long-term memory. Previously we demonstrated that aging disrupts the coordinated epigenetic response to recent experience observed in the young adult hippocampus. Here we extended that work to test the cognitive effects of a novel, brain-penetrant HDACi (EVX001688; EVX) that we confirmed yields robust, relatively long lasting dose-dependent increases in histone acetylation in the hippocampus. In young rats, acute systemic EVX administration, scheduled to yield elevated histone acetylation levels during training in a contextual fear conditioning (CFC) task, had no effect on memory retention at 24 hours at any dose examined (10, 30, or 60 mg/kg). Pretraining injection of another HDACi, sodium butyrate, also failed to affect fear memory, and CFC training itself had no influence on hippocampal histone acetylation at 1 hour in mice or two strains of rats. EVX administration before water maze training in young rats yielded a modest effect such that the middle dose produced marginally better 24-hour retention than either the low or high dose, but only a small numerical benefit relative to vehicle. Guided by those findings, a final experiment tested the influence of pretraining EVX treatment on age-related spatial memory impairment. The results, revealing no effect on performance, are consistent with the idea that effective procognitive HDACi treatments in aging may require intervention aimed at restoring coordinated epigenetic regulation rather than bulk increases in hippocampal histone acetylation. PMID:24753063

  9. Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging.

    PubMed

    Castellano, James F; Fletcher, Bonnie R; Patzke, Holger; Long, Jeffrey M; Sewal, Angila; Kim, David H; Kelley-Bell, Bennett; Rapp, Peter R

    2014-08-01

    Converging results link histone acetylation dynamics to hippocampus-dependent memory, including evidence that histone deacetylase inhibitor (HDACi) administration enhances long-term memory. Previously, we demonstrated that aging disrupts the coordinated epigenetic response to recent experience observed in the young adult hippocampus. Here, we extended that work to test the cognitive effects of a novel, brain-penetrant HDACi (EVX001688; EVX) that we confirmed yields robust, relatively long lasting dose-dependent increases in histone acetylation in the hippocampus. In young rats, acute systemic EVX administration, scheduled to yield elevated histone acetylation levels during training in a contextual fear conditioning (CFC) task, had no effect on memory retention at 24 h at any dose examined (10, 30, or 60 mg/kg). Pretraining injection of another HDACi, sodium butyrate, also failed to affect fear memory, and CFC training itself had no influence on hippocampal histone acetylation at 1 hour in mice or two strains of rats. EVX administration before water maze training in young rats yielded a modest effect such that the middle dose produced marginally better 24-h retention than either the low or high dose, but only a small numerical benefit relative to vehicle. Guided by those findings, a final experiment tested the influence of pretraining EVX treatment on age-related spatial memory impairment. The results, revealing no effect on performance, are consistent with the idea that effective procognitive HDACi treatments in aging may require intervention aimed at restoring coordinated epigenetic regulation rather than bulk increases in hippocampal histone acetylation. PMID:24753063

  10. Histone deacetylases inhibitor trichostatin A modulates the extracellular release of APE1/Ref-1

    SciTech Connect

    Choi, Sunga; Lee, Yu Ran; Park, Myoung Soo; Joo, Hee Kyoung; Cho, Eun Jung; Kim, Hyo Shin; Kim, Cuk Seong; Park, Jin Bong; Irani, Kaikobad; Jeon, Byeong Hwa

    2013-06-07

    Highlights: •Trichostatin A (TSA) increased APE1/Ref-1 secretion in HEK293 cells. •Lysine-mutated APE1/Ref-1 (K6R/K7R) was not secreted by TSA. •TSA induced cytoplasmic translocation of APE1/Ref-1. •APE1/Ref-1 is a protein whose secretion is governed by lysine acetylation. -- Abstract: Apurinic/apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) can be acetylated via post-translational modification. We investigated the effect of an inhibitor of histone deacetylases on the extracellular release of APE1/Ref-1 in HEK293 cells. Trichostatin A (TSA), an inhibitor of histone deacetylases, induced APE1/Ref-1 secretion without changing cell viability. In a fluorescence quantitative assay, the secreted APE1/Ref-1 was estimated to be about 10 ng/mL in response to TSA (1 μM). However, TSA did not induce the secretion of lysine-mutated APE1/Ref-1 (K6R/K7R). TSA also caused nuclear to cytoplasmic translocation of APE1/Ref-1. Taken together, these findings suggest that APE1/Ref-1 is a protein whose secretion is governed by lysine acetylation.

  11. Histone Deacetylase 6 Regulates Bladder Architecture and Host Susceptibility to Uropathogenic Escherichia coli

    PubMed Central

    Lewis, Adam J.; Dhakal, Bijaya K.; Liu, Ting; Mulvey, Matthew A.

    2016-01-01

    Histone deacetylase 6 (HDAC6) is a non-canonical, mostly cytosolic histone deacetylase that has a variety of interacting partners and substrates. Previous work using cell-culture based assays coupled with pharmacological inhibitors and gene-silencing approaches indicated that HDAC6 promotes the actin- and microtubule-dependent invasion of host cells by uropathogenic Escherichia coli (UPEC). These facultative intracellular pathogens are the major cause of urinary tract infections. Here, we examined the involvement of HDAC6 in bladder colonization by UPEC using HDAC6 knockout mice. Though UPEC was unable to invade HDAC6−/− cells in culture, the bacteria had an enhanced ability to colonize the bladders of mice that lacked HDAC6. This effect was transient, and by six hours post-inoculation bacterial titers in the HDAC6−/− mice were reduced to levels seen in wild type control animals. Subsequent analyses revealed that the mutant mice had greater bladder volume capacity and fluid retention, along with much higher levels of acetylated α-tubulin. In addition, infiltrating neutrophils recovered from the HDAC6−/− bladder harbored significantly more viable bacteria than their wild type counterparts. Cumulatively, these changes may negate any inhibitory effects that the lack of HDAC6 has on UPEC entry into individual host cells, and suggest roles for HDAC6 in other urological disorders such as urinary retention. PMID:26907353

  12. Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor

    SciTech Connect

    Nielsen, Tine Kragh; Hildmann, Christian; Riester, Daniel; Wegener, Dennis; Schwienhorst, Andreas; Ficner, Ralf

    2007-04-01

    The crystal structure of HDAH FB188 in complex with a trifluoromethylketone at 2.2 Å resolution is reported and compared to a previously determined inhibitor complex. Histone deacetylases (HDACs) have emerged as attractive targets in anticancer drug development. To date, a number of HDAC inhibitors have been developed and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA). Not surprisingly, structural information that can greatly enhance the design of novel HDAC inhibitors is so far only available for hydroxamic acids in complex with HDAC or HDAC-like enzymes. Here, the first structure of an enzyme complex with a nonhydroxamate HDAC inhibitor is presented. The structure of the trifluoromethyl ketone inhibitor 9,9,9-trifluoro-8-oxo-N-phenylnonanamide in complex with bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) has been determined. HDAH reveals high sequential and functional homology to human class 2 HDACs and a high structural homology to human class 1 HDACs. Comparison with the structure of HDAH in complex with SAHA reveals that the two inhibitors superimpose well. However, significant differences in binding to the active site of HDAH were observed. In the presented structure the O atom of the trifluoromethyl ketone moiety is within binding distance of the Zn atom of the enzyme and the F atoms participate in interactions with the enzyme, thereby involving more amino acids in enzyme–inhibitor binding.

  13. Histone Deacetylase Inhibitors Delivery using Nanoparticles with Intrinsic Passive Tumor Targeting Properties for Tumor Therapy

    PubMed Central

    el Bahhaj, Fatima; Denis, Iza; Pichavant, Loic; Delatouche, Régis; Collette, Floraine; Linot, Camille; Pouliquen, Daniel; Grégoire, Marc; Héroguez, Valérie; Blanquart, Christophe; Bertrand, Philippe

    2016-01-01

    Fast clearance, metabolism and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo model of cancers. Specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. In this work, we describe a simple and flexible polymeric nanoparticle platform highly targeting the tumor in vivo and triggering impressive tumor weight reduction when functionalized with HDACi. Our nanoparticles were produced by Ring-Opening Metathesis Polymerization of azido-polyethylene oxide-norbornene macromonomers and functionalized using click chemistry. Using an orthotopic model of peritoneal invasive cancer, a highly selective accumulation of the particles in the tumor was obtained. A combination of epigenetic drugs involving a pH-responsive histone deacetylase inhibitor (HDACi) polymer conjugated to these particles gave 80% reduction of tumor weight without toxicity whereas the free HDACi has no effect. Our work demonstrates that the use of a nanovector with theranostic properties leads to an optimized delivery of potent HDACi in tumor and then, to an improvement of their anti-tumor properties in vivo. PMID:27162550

  14. Hydroxamic acid derivatives of mycophenolic acid inhibit histone deacetylase at the cellular level.

    PubMed

    Batovska, Daniela I; Kim, Dong Hoon; Mitsuhashi, Shinya; Cho, Yoon Sun; Kwon, Ho Jeong; Ubukata, Makoto

    2008-10-01

    Mycophenolic acid (MPA, 1), an inhibitor of IMP-dehydrogenase (IMPDH) and a latent PPARgamma agonist, is used as an effective immunosuppressant for clinical transplantation and recently entered clinical trials in advanced multiple myeloma patients. On the other hand, suberoylanilide hydroxamic acid (SAHA), a non-specific histone deacetylase (HDAC) inhibitor, has been approved for treating cutaneous T-cell lymphoma. MPA seemed to bear a cap, a linker, and a weak metal-binding site as a latent inhibitor of HDAC. Therefore, the hydroxamic acid derivatives of mycophenolic acid having an effective metal-binding site, mycophenolic hydroxamic acid (MPHA, 2), 7-O-acetyl mycophenolic acid (7-O-Ac MPHA, 3), and 7-O-lauroyl mycophenolic hydroxamic acid (7-O-L MPHA, 4) were designed and synthesized. All these compounds inhibited histone deacetylase with IC50 values of 1, 0.9 and 0.5 microM, and cell proliferation at concentrations of 2, 1.5 and 1 microM, respectively. PMID:18838793

  15. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition.

    PubMed

    Hai, Yang; Christianson, David W

    2016-09-01

    Histone deacetylase 6 (HDAC6) is a critical target for drug design because of its role in oncogenic transformation and cancer metastasis, and is unique among all histone deacetylases in that it contains tandem catalytic domains designated CD1 and CD2. We now report the crystal structures of CD2 from Homo sapiens HDAC6 and of CD1 and CD2 from Danio rerio HDAC6. We correlated these structures with activity measurements using 13 different substrates. The catalytic activity of CD2 from both species exhibited broad substrate specificity, whereas that of CD1 was highly specific for substrates bearing C-terminal acetyllysine residues. Crystal structures of substrate complexes yielded unprecedented snapshots of the catalytic mechanism. Additionally, crystal structures of complexes with eight different inhibitors, including belinostat and panobinostat (currently used in cancer chemotherapy), the macrocyclic tetrapeptide HC toxin, and the HDAC6-specific inhibitor N-hydroxy-4-(2-((2-hydroxyethyl)(phenyl)amino)-2-oxoethyl)benzamide, revealed surprising new insight regarding changes in Zn(2+) coordination and isozyme-specific inhibition. PMID:27454933

  16. Arabidopsis DNA methyltransferase AtDNMT2 associates with histone deacetylase AtHD2s activity

    SciTech Connect

    Song, Yuan; Wu, Keqiang; Dhaubhadel, Sangeeta; An, Lizhe; Tian, Lining

    2010-05-28

    DNA methyltransferase2 (DNMT2) is always deemed to be enigmatic, because it contains highly conserved DNA methyltransferase motifs but lacks the DNA methylation catalytic capability. Here we show that Arabidopsis DNA methyltransferase2 (AtDNMT2) is localized in nucleus and associates with histone deacetylation. Bimolecular fluorescence complementation and pull-down assays show AtDNMT2 interacts with type-2 histone deacetylases (AtHD2s), a unique type of histone deacetylase family in plants. Through analyzing the expression of AtDNMT2: ss-glucuronidase (GUS) fusion protein, we demonstrate that AtDNMT2 has the ability to repress gene expression at transcription level. Meanwhile, the expression of AtDNMT2 gene is altered in athd2c mutant plants. We propose that AtDNMT2 possibly involves in the activity of histone deacetylation and plant epigenetic regulatory network.

  17. Histone deacetylase inhibitor trichostatin A and proteasome inhibitor PS-341 synergistically induce apoptosis in pancreatic cancer cells

    SciTech Connect

    Bai Jirong . E-mail: jbai@bidmc.harvard.edu; Demirjian, Aram; Sui Jianhua; Marasco, Wayne; Callery, Mark P. . E-mail: mcallery@bidmc.harvard.ede

    2006-10-06

    Pancreatic cancer is a common and lethal malignancy. Pancreatic cancer cells overexpress multiple anti-apoptotic factors and death receptor decoys, and are strongly resistant to radiation and to 5-fluorouracil (5-FU)- or gemcitabine (Gem)-based chemotherapy regimens. We have found that low-dose proteasome inhibitor PS-341 and histone deacetylase inhibitor trichostatin A (TSA) synergistically induce cytotoxicity in a panel of eight diverse pancreatic cancer cell lines. Combining TSA with PS-341 effectively inactivated NF{kappa}B signaling, downregulated the predominant endogenous anti-apoptotic factor Bcl-XL overexpression, and disrupted MAP kinase pathway. The combined drug regimen effectively inflicted an average of 71.5% apoptotic cell death (55.2-80%) in diverse pancreatic cancer cell lines by activating the intrinsic apoptotic pathway. Conclusion: the TSA/PS-341 regimen may represent a potential novel therapeutic strategy for pancreatic cancer.

  18. Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone H4 Epigenome and Reduces Akt Phosphorylation*

    PubMed Central

    Dudakovic, Amel; Evans, Jared M.; Li, Ying; Middha, Sumit; McGee-Lawrence, Meghan E.; van Wijnen, Andre J.; Westendorf, Jennifer J.

    2013-01-01

    Bone has remarkable regenerative capacity, but this ability diminishes during aging. Histone deacetylase inhibitors (HDIs) promote terminal osteoblast differentiation and extracellular matrix production in culture. The epigenetic events altered by HDIs in osteoblasts may hold clues for the development of new anabolic treatments for osteoporosis and other conditions of low bone mass. To assess how HDIs affect the epigenome of committed osteoblasts, MC3T3 cells were treated with suberoylanilide hydroxamic acid (SAHA) and subjected to microarray gene expression profiling and high-throughput ChIP-Seq analysis. As expected, SAHA induced differentiation and matrix calcification of osteoblasts in vitro. ChIP-Seq analysis revealed that SAHA increased histone H4 acetylation genome-wide and in differentially regulated genes, except for the 500 bp upstream of transcriptional start sites. Pathway analysis indicated that SAHA increased the expression of insulin signaling modulators, including Slc9a3r1. SAHA decreased phosphorylation of insulin receptor β, Akt, and the Akt substrate FoxO1, resulting in FoxO1 stabilization. Thus, SAHA induces genome-wide H4 acetylation and modulates the insulin/Akt/FoxO1 signaling axis, whereas it promotes terminal osteoblast differentiation in vitro. PMID:23940046

  19. Investigation on the ZBG-functionality of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase inhibitors.

    PubMed

    Musso, Loana; Cincinelli, Raffaella; Zuco, Valentina; Zunino, Franco; Nurisso, Alessandra; Cuendet, Muriel; Giannini, Giuseppe; Vesci, Loredana; Pisano, Claudio; Dallavalle, Sabrina

    2015-10-15

    A series of alternative Zn-binding groups were explored in the design of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds were less effective than the parent hydroxamic acid. However, the profile of activity shown by the analog bearing a hydroxyurea head group, makes this derivative promising for further investigation. PMID:26376355

  20. Cloning, expression, and biochemical characterization of a new histone deacetylase-like protein from Thermus caldophilus GK24

    SciTech Connect

    Song, Young Mi; Kim, You Sun; Kim, Dooil; Lee, Dae Sil; Kwon, Ho Jeong . E-mail: kwonhj@yonsei.ac.kr

    2007-09-14

    Histone deactylases (HDACs) are members of an ancient enzyme family found in eukaryotes as well as in prokaryotes such as archaebacteria and eubacteria. We here report a new histone deacetylase (Tca HDAC) that was cloned from the genomic library of Thermus caldophilus GK24 based on homology analysis with human histone deacetylase1 (HDAC1). The gene contains an open reading frame encoding 375 amino acids with a calculated molecular mass of 42,188 Da and the deduced amino acid sequence of Tca HDAC showed a 31% homology to human HDAC1. The Tca HDAC gene was over-expressed in Escherichia coli using a Glutathione-S transferase (GST) fusion vector (pGEX-4T-1) and the purified protein showed a deacetylase activity toward the fluorogenic substrate for HDAC. Moreover, the enzyme activity was inhibited by trichostatin A, a specific HDAC inhibitor, in a dose-dependent manner. Optimum temperature and pH of the enzyme was found to be approximately 70 {sup o}C and 7.0, respectively. In addition, zinc ion is required for catalytic activity of the enzyme. Together, these data demonstrate that Tca HDAC is a new histone deacetylase-like enzyme from T. caldophilus GK24 and will be a useful tool for deciphering the role of HDAC in the prokaryote and development of new biochemical reactions.

  1. Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex

    PubMed Central

    Clark, Michael D.; Marcum, Ryan; Graveline, Richard; Chan, Clarence W.; Xie, Tao; Chen, Zhonglei; Ding, Yujia; Zhang, Yongbo; Mondragón, Alfonso; David, Gregory; Radhakrishnan, Ishwar

    2015-01-01

    Acetylation is correlated with chromatin decondensation and transcriptional activation, but its regulation by histone deacetylase (HDAC)-bearing corepressor complexes is poorly understood. Here, we describe the mechanism of assembly of the mammalian Sin3L/Rpd3L complex facilitated by Sds3, a conserved subunit deemed critical for proper assembly. Sds3 engages a globular, helical region of the HDAC interaction domain (HID) of the scaffolding protein Sin3A through a bipartite motif comprising a helix and an adjacent extended segment. Sds3 dimerizes through not only one of the predicted coiled-coil motifs but also, the segment preceding it, forming an ∼150-Å-long antiparallel dimer. Contrary to previous findings in yeast, Sin3A rather than Sds3 functions in recruiting HDAC1 into the complex by engaging the latter through a highly conserved segment adjacent to the helical HID subdomain. In the resulting model for the ternary complex, the two copies of the HDACs are situated distally and dynamically because of a natively unstructured linker connecting the dimerization domain and the Sin3A interaction domain of Sds3; these features contrast with the static organization described previously for the NuRD (nucleosome remodeling and deacetylase) complex. The Sds3 linker features several conserved basic residues that could potentially maintain the complex on chromatin by nonspecific interactions with DNA after initial recruitment by sequence-specific DNA-binding repressors. PMID:26124119

  2. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, attenuates postoperative cognitive dysfunction in aging mice

    PubMed Central

    Jia, Min; Liu, Wen-Xue; Sun, He-Liang; Chang, Yan-Qing; Yang, Jiao-Jiao; Ji, Mu-Huo; Yang, Jian-Jun; Feng, Chen-Zhuo

    2015-01-01

    Postoperative cognitive dysfunction (POCD) is a recognized clinical entity characterized with cognitive deficits after anesthesia and surgery, especially in aged patients. Previous studies have shown that histone acetylation plays a key role in hippocampal synaptic plasticity and memory formation. However, its role in POCD remains to be determined. Here, we show that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, attenuates POCD in aging Mice. After exposed to the laparotomy, a surgical procedure involving an incision into abdominal walls to examine the abdominal organs, 16- but not 3-month old male C57BL/6 mice developed obvious cognitive impairments in the test of long-term contextual fear conditioning. Intracerebroventricular (i.c.v.) injection of SAHA at the dose of (20 μg/2 μl) 3 h before and daily after the laparotomy restored the laparotomy-induced reduction of hippocampal acetyl-H3 and acetyl-H4 levels and significantly attenuated the hippocampus-dependent long-term memory (LTM) impairments in 16-month old mice. SAHA also reduced the expression of cleaved caspase-3, inducible nitric oxide synthase (iNOS) and N-methyl-D-aspartate (NMDA) receptor-calcium/calmodulin dependent kinase II (CaMKII) pathway, and increased the expression of brain-derived neurotrophic factor (BDNF), synapsin 1, and postsynaptic density 95 (PSD95). Taken together, our data suggest that the decrease of histone acetylation contributes to POCD and may serve as a target to improve the neurological outcome of POCD. PMID:26441515

  3. Histone deacetylase 1 and 2 regulate Wnt and p53 pathways in the ureteric bud epithelium

    PubMed Central

    Chen, Shaowei; Yao, Xiao; Li, Yuwen; Saifudeen, Zubaida; Bachvarov, Dimcho; El-Dahr, Samir S.

    2015-01-01

    Histone deacetylases (HDACs) regulate a broad range of biological processes through removal of acetyl groups from histones as well as non-histone proteins. Our previous studies showed that Hdac1 and Hdac2 are bound to promoters of key renal developmental regulators and that HDAC activity is required for embryonic kidney gene expression. However, the existence of many HDAC isoforms in embryonic kidneys raises questions concerning the possible specificity or redundancy of their functions. We report here that targeted deletion of both the Hdac1 and Hdac2 genes from the ureteric bud (UB) cell lineage of mice causes bilateral renal hypodysplasia. One copy of either Hdac1 or Hdac2 is sufficient to sustain normal renal development. In addition to defective cell proliferation and survival, genome-wide transcriptional profiling revealed that the canonical Wnt signaling pathway is specifically impaired in UBHdac1,2−/− kidneys. Our results also demonstrate that loss of Hdac1 and Hdac2 in the UB epithelium leads to marked hyperacetylation of the tumor suppressor protein p53 on lysine 370, 379 and 383; these post-translational modifications are known to boost p53 stability and transcriptional activity. Genetic deletion of p53 partially rescues the development of UBHdac1,2−/− kidneys. Together, these data indicate that Hdac1 and Hdac2 are crucial for kidney development. They perform redundant, yet essential, cell lineage-autonomous functions via p53-dependent and -independent pathways. PMID:25758227

  4. The Microtubule-associated Histone Deacetylase 6 (HDAC6) Regulates Epidermal Growth Factor Receptor (EGFR) Endocytic Trafficking and Degradation*

    PubMed Central

    Gao, Ya-sheng; Hubbert, Charlotte C.; Yao, Tso-Pang

    2010-01-01

    Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase with tubulin deacetylase activity, and it binds dynein motors. Recent studies revealed that microtubule acetylation affects the affinity and processivity of microtubule motors. These unique properties implicate a role for HDAC6 in intracellular organelle transport. Here, we show that HDAC6 associates with the endosomal compartments and controls epidermal growth factor receptor (EGFR) trafficking and degradation. We found that loss of HDAC6 promoted EGFR degradation. Mechanistically, HDAC6 deficiency did not cause aberrant EGFR internalization and recycling. Rather, it resulted in accelerated segregation of EGFR from early endosomes and premature delivery of EGFR to the late endosomal and lysosomal compartments. The deregulated EGFR endocytic trafficking was accompanied by an increase in microtubule-dependent movement of EGFR-bearing vesicles, revealing a novel regulation of EGFR vesicular trafficking and degradation by the microtubule deacetylase HDAC6. PMID:20133936

  5. Dual inhibition of histone deacetylases and phosphoinositide 3-kinases: effects on Burkitt lymphoma cell growth and migration.

    PubMed

    Ferreira, Ana Carolina dos Santos; de-Freitas-Junior, Julio Cesar Madureira; Morgado-Díaz, Jose Andres; Ridley, Anne J; Klumb, Claudete Esteves

    2016-04-01

    Burkitt lymphoma is a highly aggressive non-Hodgkin lymphoma that is characterized by MYC deregulation. Recently, the PI3K pathway has emerged as a cooperative prosurvival mechanism in Burkitt lymphoma. Despite the highly successful results of treatment that use high-dose chemotherapy regimens in pediatric Burkitt lymphoma patients, the survival rate of pediatric patients with progressive or recurrent disease is low. PI3Ks are also known to regulate cell migration, and abnormal cell migration may contribute to cancer progression and dissemination in Burkitt lymphoma. Little is known about Burkitt lymphoma cell migration, but the cooperation between MYC and PI3K in Burkitt lymphoma pathogenesis suggests that a drug combination could be used to target the different steps involved in Burkitt lymphoma cell dissemination and disease progression. The aim of this study was to investigate the effects of the histone deacetylase inhibitor suberoylanilide hydroxamic acid combined with the PI3K inhibitor LY294002 on Burkitt lymphoma cell growth and migration. The combination enhanced the cell growth inhibition and cell-cycle arrest induced by the PI3K inhibitor or histone deacetylase inhibitor individually. Moreover, histone deacetylase inhibitor/PI3K inhibitor cotreatment suppressed Burkitt lymphoma cell migration and decreased cell polarization, Akt and ERK1/2 phosphorylation, and leads to RhoB induction. In summary, the histone deacetylase inhibitor/PI3Ki combination inhibits cell proliferation and migration via alterations in PI3K signaling and histone deacetylase activity, which is involved in the acetylation of α-tubulin and the regulation of RhoB expression. PMID:26561567

  6. Histone deacetylase inhibitors stimulate histone H3 lysine 4 methylation in part via transcriptional repression of histone H3 lysine 4 demethylases.

    PubMed

    Huang, Po-Hsien; Chen, Chun-Han; Chou, Chih-Chien; Sargeant, Aaron M; Kulp, Samuel K; Teng, Che-Ming; Byrd, John C; Chen, Ching-Shih

    2011-01-01

    This study investigates the mechanism by which histone deacetylase (HDAC) inhibitors up-regulate histone H3 lysine 4 (H3K4) methylation. Exposure of LNCaP prostate cancer cells and the prostate tissue of transgenic adenocarcinoma of the mouse prostate mice to the pan- and class I HDAC inhibitors (S)-(+)-N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide (AR42), N-(2-aminophenyl)-4-[N-(pyridine-3-yl-methoxycarbonyl)-aminomethyl]-benzamide (MS-275), and vorinostat led to differential increases in H3K4 methylation. Chromatin immunoprecipitation shows that this accumulation of methylated H3K4 occurred in conjunction with decreases in the amount of the H3K4 demethylase RBP2 at the promoter of genes associated with tumor suppression and differentiation, including KLF4 and E-cadherin. This finding, together with the HDAC inhibitor-induced up-regulation of KLF4 and E-cadherin, suggests that HDAC inhibitors could activate the expression of these genes through changes in histone methylation status. Evidence indicates that this up-regulation of H3K4 methylation was attributable to the suppressive effect of these HDAC inhibitors on the expression of RBP2 and other JARID1 family histone demethylases, including PLU-1, SMCX, and LSD1, via the down-regulation of Sp1 expression. Moreover, shRNA-mediated silencing of the class I HDAC isozymes 1, 2, 3, and 8, but not that of the class II isozyme HDAC6, mimicked the drug effects on H3K4 methylation and H3K4 demethylases, which could be reversed by ectopic Sp1 expression. These data suggest a cross-talk mechanism between HDACs and H3K4 demethylases via Sp1-mediated transcriptional regulation, which underlies the complexity of the functional role of HDACs in the regulation of histone modifications. PMID:20959362

  7. Histone deacetylase inhibitors and transforming growth factor-beta induce 15-hydroxyprostaglandin dehydrogenase expression in human lung adenocarcinoma cells.

    PubMed

    Tong, Min; Ding, Yunfei; Tai, Hsin-Hsiung

    2006-09-14

    Histone deacetylase (HDAC) inhibitors have been actively exploited as potential anticancer agents. To identify gene targets of HDAC inhibitors, we found that HDAC inhibitors such as sodium butyrate, scriptaid, apicidin and oxamflatin induced the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a potential cyclooxygenase-2 (COX-2) antagonist and tumor suppressor, in a time and concentration dependent manner in A549 and H1435 lung adenocarcinoma cells. Detailed analyses indicated that HDAC inhibitors activated the 15-PGDH promoter-luciferase reporter construct in transfected A549 cells. A representative HDAC inhibitor, scriptaid, and its negative structural analog control, nullscript, were further evaluated at the chromatin level. Scriptaid but not nullscript induced a significant accumulation of acetylated histones H3 and H4 which were associated with the 15-PGDH promoter as determined by chromatin immunoprecipitation assay. Transforming growth factor-beta1 (TGF-beta1) also induced the expression of 15-PGDH in a time and concentration dependent manner in A549 and H1435 cells. Induction of 15-PGDH expression by TGF-beta1 was synergistically stimulated by the addition of Wnt3A which was inactive by itself. However, combination of TGF-beta and an HDAC inhibitor, scriptaid, only resulted in an additive effect. Together, our results indicate that 15-PGDH is one of the target genes that HDAC inhibitors and TGF-beta may induce to exhibit tumor suppressive effects. PMID:16844092

  8. Histone Deacetylase Inhibitors Inhibit Rhabdomyosarcoma by Reactive Oxygen Species-Dependent Targeting of Specificity Protein Transcription Factors.

    PubMed

    Hedrick, Erik; Crose, Lisa; Linardic, Corinne M; Safe, Stephen

    2015-09-01

    The two major types of rhabdomyosarcoma (RMS) are predominantly diagnosed in children, namely embryonal (ERMS) and alveolar (ARMS) RMS, and patients are treated with cytotoxic drugs, which results in multiple toxic side effects later in life. Therefore, development of innovative chemotherapeutic strategies is imperative, and a recent genomic analysis suggested the potential efficacy of reactive oxygen species (ROS)-inducing agents. Here, we demonstrate the efficacy of the potent histone deacetylase (HDAC) inhibitors, panobinostat and vorinostat, as agents that inhibit RMS tumor growth in vivo, induce apoptosis, and inhibit invasion of RD and Rh30 RMS cell lines. These effects are due to epigenetic repression of cMyc, which leads to decreased expression of cMyc-regulated miRs-17, -20a, and -27a; upregulation of ZBTB4, ZBTB10, and ZBTB34; and subsequent downregulation of Sp transcription factors. We also show that inhibition of RMS cell growth, survival and invasion, and repression of Sp transcription factors by the HDAC inhibitors are independent of histone acetylation but reversible after cotreatment with the antioxidant glutathione. These results show a novel ROS-dependent mechanism of antineoplastic activity for panobinostat and vorinostat that lies outside of their canonical HDAC-inhibitory activity and demonstrates the potential clinical utility for treating RMS patients with ROS-inducing agents. PMID:26162688

  9. Cell Signaling Switches HOX-PBX Complexes from Repressors to Activators of Transcription Mediated by Histone Deacetylases and Histone Acetyltransferases

    PubMed Central

    Saleh, Maya; Rambaldi, Isabel; Yang, Xiang-Jiao; Featherstone, Mark S.

    2000-01-01

    The Hoxb1 autoregulatory element comprises three HOX-PBX binding sites. Despite the presence of HOXB1 and PBX1, this enhancer fails to activate reporter gene expression in retinoic acid-treated P19 cell monolayers. Activation requires cell aggregation in addition to RA. This suggests that HOX-PBX complexes may repress transcription under some conditions. Consistent with this, multimerized HOX-PBX binding sites repress reporter gene expression in HEK293 cells. We provide a mechanistic basis for repressor function by demonstrating that a corepressor complex, including histone deacetylases (HDACs) 1 and 3, mSIN3B, and N-CoR/SMRT, interacts with PBX1A. We map a site of interaction with HDAC1 to the PBX1 N terminus and show that the PBX partner is required for repression by the HOX-PBX complex. Treatment with the deacetylase inhibitor trichostatin A not only relieves repression but also converts the HOX-PBX complex to a net activator of transcription. We show that this activation function is mediated by the recruitment of the coactivator CREB-binding protein by the HOX partner. Interestingly, HOX-PBX complexes are switched from transcriptional repressors to activators in response to protein kinase A signaling or cell aggregation. Together, our results suggest a model whereby the HOX-PBX complex can act as a repressor or activator of transcription via association with corepressors and coactivators. The model implies that cell signaling is a direct determinant of HOX-PBX function in the patterning of the animal embryo. PMID:11046157

  10. Histone Deacetylase 7 Promotes PML Sumoylation and Is Essential for PML Nuclear Body Formation▿ †

    PubMed Central

    Gao, Chengzhuo; Ho, Chun-Chen; Reineke, Erin; Lam, Minh; Cheng, Xiwen; Stanya, Kristopher J.; Liu, Yu; Chakraborty, Sharmistha; Shih, Hsiu-Ming; Kao, Hung-Ying

    2008-01-01

    Promyelocytic leukemia protein (PML) sumoylation has been proposed to control the formation of PML nuclear bodies (NBs) and is crucial for PML-dependent cellular processes, including apoptosis and transcriptional regulation. However, the regulatory mechanisms of PML sumoylation and its specific roles in the formation of PML NBs remain largely unknown. Here, we show that histone deacetylase 7 (HDAC7) knockdown reduces the size and the number of the PML NBs in human umbilical vein endothelial cells (HUVECs). HDAC7 coexpression stimulates PML sumoylation independent of its HDAC activity. Furthermore, HDAC7 associates with the E2 SUMO ligase, Ubc9, and stimulates PML sumoylation in vitro, suggesting that it possesses a SUMO E3 ligase-like activity to promote PML sumoylation. Importantly, HDAC7 knockdown inhibits tumor necrosis factor alpha-induced PML sumoylation and the formation of PML NBs in HUVECs. These results demonstrate a novel function of HDAC7 and provide a regulatory mechanism of PML sumoylation. PMID:18625722

  11. Interrogating Substrate Selectivity and Composition of Endogenous Histone Deacetylase Complexes with Chemical Probes.

    PubMed

    Dose, Alexander; Sindlinger, Julia; Bierlmeier, Jan; Bakirbas, Ahmet; Schulze-Osthoff, Klaus; Einsele-Scholz, Stephanie; Hartl, Markus; Essmann, Frank; Finkemeier, Iris; Schwarzer, Dirk

    2016-01-18

    Histone deacetylases (HDACs) regulate the function and activity of numerous cellular proteins by removing acetylation marks from regulatory lysine residues. We have developed peptide-based HDAC probes that contain hydroxamate amino acids of various lengths to replace modified lysine residues in the context of known acetylation sites. The interaction profiles of all human HDACs were studied with three sets of probes, which derived from different acetylation sites, and sequence context was found to have a strong impact on substrate recognition and composition of HDAC complexes. By investigating K382 acetylation of the tumor suppressor p53 as an example, we further demonstrate that the interaction profiles reflect the catalytic activities of respective HDACs. These results underline the utility of the newly established probes for deciphering not only activity, but also substrate selectivity and composition of endogenous HDAC complexes, which can hardly be achieved otherwise. PMID:26662792

  12. Histone deacetylase 1 is required for the development of the zebrafish inner ear

    PubMed Central

    He, Yingzi; Tang, Dongmei; Li, Wenyan; Chai, Renjie; Li, Huawei

    2016-01-01

    Histone deacetylase 1 (HDAC1) has been reported to be important for multiple aspects of normal embryonic development, but little is known about its function in the development of mechanosensory organs. Here, we first confirmed that HDAC1 is expressed in the developing otic vesicles of zebrafish by whole-mount in situ hybridization. Knockdown of HDAC1 using antisense morpholino oligonucleotides in zebrafish embryos induced smaller otic vesicles, abnormal otoliths, malformed or absent semicircular canals, and fewer sensory hair cells. HDAC1 loss of function also caused attenuated expression of a subset of key genes required for otic vesicle formation during development. Morpholino-mediated knockdown of HDAC1 resulted in decreased expression of members of the Fgf family in the otic vesicles, suggesting that HDAC1 is involved in the development of the inner ear through regulation of Fgf signaling pathways. Taken together, our results indicate that HDAC1 plays an important role in otic vesicle formation. PMID:26832938

  13. Inhibition of SRC-3 enhances sensitivity of human cancer cells to histone deacetylase inhibitors.

    PubMed

    Zou, Zhengzhi; Luo, Xiaoyong; Nie, Peipei; Wu, Baoyan; Zhang, Tao; Wei, Yanchun; Wang, Wenyi; Geng, Guojun; Jiang, Jie; Mi, Yanjun

    2016-09-01

    SRC-3 is widely expressed in multiple tumor types and involved in cancer cell proliferation and apoptosis. Histone deacetylase (HDAC) inhibitors are promising antitumor drugs. However, the poor efficacy of HDAC inhibitors in solid tumors has restricted its further clinical application. Here, we reported the novel finding that depletion of SRC-3 enhanced sensitivity of breast and lung cancer cells to HDAC inhibitors (SAHA and romidepsin). In contrast, overexpression of SRC-3 decreased SAHA-induced cancer cell apoptosis. Furthermore, we found that SRC-3 inhibitor bufalin increased cancer cell apoptosis induced by HDAC inhibitors. The combination of bufalin and SAHA was particular efficient in attenuating AKT activation and reducing Bcl-2 levels. Taken together, these accumulating data might guide development of new breast and lung cancer therapies. PMID:27425252

  14. Synthesis and Structure Activity Relationship of 3-Hydroxypyridin-2-thione Based Histone Deacetylase Inhibitors

    PubMed Central

    Sodji, Quaovi H.; Patil, Vishal; Kornacki, James R.; Mrksich, Milan; Oyelere, Adegboyega K.

    2014-01-01

    We have previously identified 3-hydroxypyridin-2-thione (3HPT) as a novel zinc binding group for histone deacetylase (HDAC) inhibition. Early structure activity relationship (SAR) studies led to various small molecules possessing selective inhibitory activity against HDAC6 or HDAC8 but are devoid of HDAC1 inhibition. To further delineate the depth of the SAR of 3HPT-derived HDAC inhibitors (HDACi), we have extended the SAR studies to include the linker region and the surface recognition group to optimize the HDAC inhibition. The current efforts resulted in the identification of two lead compounds 10d and 14e with potent HDAC6 and HDAC8 activities, but that are inactive against HDAC1. These new HDACi possess anti-cancer activities against various cancer cell lines including Jurkat J-γ1 against which SAHA and the previously disclosed 3HPT-derived HDACi were inactive. PMID:24304348

  15. Search for novel histone deacetylase inhibitors. Part II: design and synthesis of novel isoferulic acid derivatives.

    PubMed

    Lu, Wen; Wang, Fang; Zhang, Tao; Dong, Jinyun; Gao, Hongping; Su, Ping; Shi, Yaling; Zhang, Jie

    2014-05-01

    Previously, we described the discovery of potent ferulic acid-based histone deacetylase inhibitors (HDACIs) with halogeno-acetanilide as novel surface recognition moiety (SRM). In order to improve the affinity and activity of these HDACIs, twenty seven isoferulic acid derivatives were described herein. The majority of title compounds displayed potent HDAC inhibitory activity. In particular, IF5 and IF6 exhibited significant enzymatic inhibitory activities, with IC50 values of 0.73 ± 0.08 and 0.57 ± 0.16 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against human cancer cells. Especially, IF6 displayed promising profile as an antitumor candidate with IC50 value of 3.91 ± 0.97 μM against HeLa cells. The results indicated that these isoferulic acid derivatives could serve as promising lead compounds for further optimization. PMID:24702857

  16. Development of novel ferulic acid derivatives as potent histone deacetylase inhibitors.

    PubMed

    Wang, Fang; Lu, Wen; Zhang, Tao; Dong, Jinyun; Gao, Hongping; Li, Pengfei; Wang, Sicen; Zhang, Jie

    2013-11-15

    Histone deacetylase inhibitors (HDACIs) offer a promising strategy for cancer therapy. The discovery of potent ferulic acid-based HDACIs with hydroxamic acid or 2-aminobenzamide group as zinc binding group was reported. The halogeno-acetanilide was introduced as novel surface recognition moiety (SRM). The majority of title compounds displayed potent HDAC inhibitory activity. In particular, FA6 and FA16 exhibited significant enzymatic inhibitory activities, with IC50 values of 3.94 and 2.82 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against a panel of human cancer cells. FA17 displayed promising profile as an antitumor candidate. The results indicated that these ferulic acid derivatives could serve as promising lead compounds for further optimization. PMID:24095016

  17. Differential Regulation of Telomerase Reverse Transcriptase Promoter Activation and Protein Degradation by Histone Deacetylase Inhibition.

    PubMed

    Qing, Hua; Aono, Jun; Findeisen, Hannes M; Jones, Karrie L; Heywood, Elizabeth B; Bruemmer, Dennis

    2016-06-01

    Telomerase reverse transcriptase (TERT) maintains telomeres and is rate limiting for replicative life span. While most somatic tissues silence TERT transcription resulting in telomere shortening, cells derived from cancer or cardiovascular diseases express TERT and activate telomerase. In the present study, we demonstrate that histone deacetylase (HDAC) inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein abundance through enhanced degradation, which decreases telomerase activity and induces senescence. Finally, we demonstrate that HDAC inhibition decreases TERT expression during vascular remodeling in vivo. These data illustrate a differential regulation of TERT transcription and protein stability by HDAC inhibition and suggest that TERT may constitute an important target for the anti-proliferative efficacy of HDAC inhibitors. PMID:26505494

  18. Computational design of a time-dependent histone deacetylase 2 selective inhibitor.

    PubMed

    Zhou, Jingwei; Li, Min; Chen, Nanhao; Wang, Shenglong; Luo, Hai-Bin; Zhang, Yingkai; Wu, Ruibo

    2015-03-20

    Development of isoform-selective histone deacetylase (HDAC) inhibitors is of great biological and medical interest. Among 11 zinc-dependent HDAC isoforms, it is particularly challenging to achieve isoform inhibition selectivity between HDAC1 and HDAC2 due to their very high structural similarities. In this work, by developing and applying a novel de novo reaction-mechanism-based inhibitor design strategy to exploit the reactivity difference, we have discovered the first HDAC2-selective inhibitor, β-hydroxymethyl chalcone. Our bioassay experiments show that this new compound has a unique time-dependent selective inhibition on HDAC2, leading to about 20-fold isoform-selectivity against HDAC1. Furthermore, our ab initio QM/MM molecular dynamics simulations, a state-of-the-art approach to study reactions in biological systems, have elucidated how the β-hydroxymethyl chalcone can achieve the distinct time-dependent inhibition toward HDAC2. PMID:25546141

  19. A Photoactivatable Platinum(IV) Complex Targeting Genomic DNA and Histone Deacetylases.

    PubMed

    Kasparkova, Jana; Kostrhunova, Hana; Novakova, Olga; Křikavová, Radka; Vančo, Ján; Trávníček, Zdeněk; Brabec, Viktor

    2015-11-23

    We report toxic effects of a photoactivatable platinum(IV) complex conjugated with suberoyl-bis-hydroxamic acid in tumor cells. The conjugate exerts, after photoactivation, two functions: activity as both a platinum(II) anticancer drug and histone deacetylase (HDAC) inhibitor in cancer cells. This approach relies on the use of a Pt(IV) pro-drug, acting by two independent mechanisms of biological action in a cooperative manner, which can be selectively photoactivated to a cytotoxic species in and around a tumor, thereby increasing selectivity towards cancer cells. These results suggest that this strategy is a valuable route to design new platinum agents with higher efficacy for photodynamic anticancer chemotherapy. PMID:26458068

  20. Anti-Inflammatory Effects of Spirulina platensis Extract via the Modulation of Histone Deacetylases.

    PubMed

    Pham, Tho X; Park, Young-Ki; Lee, Ji-Young

    2016-01-01

    We previously demonstrated that the organic extract of Spirulina platensis (SPE), an edible blue-green alga, possesses potent anti-inflammatory effects. In this study, we investigated if the regulation of histone deacetylases (HDACs) play a role in the anti-inflammatory effect of SPE in macrophages. Treatment of macrophages with SPE rapidly and dose-dependently reduced HDAC2, 3, and 4 proteins which preceded decreases in their mRNA levels. Degradation of HDAC4 protein was attenuated in the presence of inhibitors of calpain proteases, lysosomal acidification, and Ca(2+)/calmodulin-dependent protein kinase II, respectively, but not a proteasome inhibitor. Acetylated histone H3 was increased in SPE-treated macrophages to a similar level as macrophages treated with a pan-HDAC inhibitor, with concomitant inhibition of inflammatory gene expression upon LPS stimulation. Knockdown of HDAC3 increased basal and LPS-induced pro-inflammatory gene expression, while HDAC4 knockdown increased basal expression of interleukin-1β (IL-1β), but attenuated LPS-induced inflammatory gene expression. Chromatin immunoprecipitation showed that SPE decreased p65 binding and H3K9/K14 acetylation at the Il-1β and tumor necrosis factor α (Tnfα) promoters. Our results suggest that SPE increased global histone H3 acetylation by facilitating HDAC protein degradation, but decreases histone H3K9/K14 acetylation and p65 binding at the promoters of Il-1β and Tnfα to exert its anti-inflammatory effect. PMID:27338466

  1. Anti-Inflammatory Effects of Spirulina platensis Extract via the Modulation of Histone Deacetylases

    PubMed Central

    Pham, Tho X.; Park, Young-Ki; Lee, Ji-Young

    2016-01-01

    We previously demonstrated that the organic extract of Spirulina platensis (SPE), an edible blue-green alga, possesses potent anti-inflammatory effects. In this study, we investigated if the regulation of histone deacetylases (HDACs) play a role in the anti-inflammatory effect of SPE in macrophages. Treatment of macrophages with SPE rapidly and dose-dependently reduced HDAC2, 3, and 4 proteins which preceded decreases in their mRNA levels. Degradation of HDAC4 protein was attenuated in the presence of inhibitors of calpain proteases, lysosomal acidification, and Ca2+/calmodulin-dependent protein kinase II, respectively, but not a proteasome inhibitor. Acetylated histone H3 was increased in SPE-treated macrophages to a similar level as macrophages treated with a pan-HDAC inhibitor, with concomitant inhibition of inflammatory gene expression upon LPS stimulation. Knockdown of HDAC3 increased basal and LPS-induced pro-inflammatory gene expression, while HDAC4 knockdown increased basal expression of interleukin-1β (IL-1β), but attenuated LPS-induced inflammatory gene expression. Chromatin immunoprecipitation showed that SPE decreased p65 binding and H3K9/K14 acetylation at the Il-1β and tumor necrosis factor α (Tnfα) promoters. Our results suggest that SPE increased global histone H3 acetylation by facilitating HDAC protein degradation, but decreases histone H3K9/K14 acetylation and p65 binding at the promoters of Il-1β and Tnfα to exert its anti-inflammatory effect. PMID:27338466

  2. Deletion of Histone Deacetylase 7 in Osteoclasts Decreases Bone Mass in Mice by Interactions with MITF

    PubMed Central

    Stemig, Melissa; Astelford, Kristina; Emery, Ann; Cho, Jangyeun J.; Allen, Ben; Huang, Tsang-hai; Gopalakrishnan, Rajaram; Mansky, Kim C.; Jensen, Eric D.

    2015-01-01

    Molecular regulators of osteoclast formation and function are an important area of research due to the central role of osteoclasts in bone resorption. Transcription factors such as MITF are essential for osteoclast generation by regulating expression of the genes required for cellular differentiation and resorptive function. We recently reported that histone deacetylase 7 (HDAC7) binds to and represses the transcriptional activity of MITF in osteoclasts, and that loss of HDAC7 in vitro accelerated osteoclastogenesis. In the current study, we extend this initial observation by showing that conditional deletion of HDAC7 in osteoclasts of mice leads to an in vivo enhancement in osteoclast formation, associated with increased bone resorption and lower bone mass. Expression of multiple MITF target genes is increased in bone marrow derived osteoclast cultures from the HDAC7 knockout mice. Interestingly, multiple regions of the HDAC7 amino-terminus can bind to MITF or exert repressive activity. Moreover, mutation or deletion of the HDAC7 conserved deacetylase catalytic domain had little effect on repressive function. These observations identify HDAC7 in osteoclasts as an important molecular regulator of MITF activity and bone homeostasis, but also highlight a gap in our understanding of exactly how HDAC7 functions as a corepressor. PMID:25875108

  3. Mitotic Activation of a Novel Histone Deacetylase 3-Linker Histone H1.3 Protein Complex by Protein Kinase CK2*

    PubMed Central

    Patil, Hemangi; Wilks, Carrie; Gonzalez, Rhiannon W.; Dhanireddy, Sudheer; Conrad-Webb, Heather; Bergel, Michael

    2016-01-01

    Histone deacetylase 3 (HDAC3) and linker histone H1 are involved in both chromatin compaction and the regulation of mitotic progression. However, the mechanisms by which HDAC3 and H1 regulate mitosis and the factors controlling HDAC3 and H1 activity during mitosis are unclear. Furthermore, as of now, no association between class I, II, or IV (non-sirtuin) HDACs and linker histones has been reported. Here we describe a novel HDAC3-H1.3 complex containing silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and nuclear receptor corepressor 1 (N-CoR) that accumulated in synchronized HeLa cells in late G2 phase and mitosis. Nonetheless, the deacetylation activity by HDAC3 in the complex was evident only in mitotic complexes. HDAC3 associated with H1.3 was highly phosphorylated on Ser-424 only during mitosis. Isolation of inactive HDAC3-H1.3 complexes from late G2 phase cells, and phosphorylation of HDAC3 in the complexes at serine 424 by protein kinase CK2 (also known as casein kinase 2) activated the HDAC3 in vitro. In vivo, CK2α and CK2α' double knockdown cells demonstrated a significant decrease in HDAC3 Ser-424 phosphorylation during mitosis. HDAC3 and H1.3 co-localized in between the chromosomes, with polar microtubules and spindle poles during metaphase through telophase, and partially co-localized with chromatin during prophase and interphase. H1 has been reported previously to associate with microtubules and, therefore, could potentially function in targeting HDAC3 to the microtubules. We suggest that phosphorylation of HDAC3 in the complex by CK2 during mitosis activates the complex for a dual role: compaction of the mitotic chromatin and regulation of polar microtubules dynamic instability. PMID:26663086

  4. The histone deacetylase (HDAC) inhibitor valproic acid reduces ethanol consumption and ethanol-conditioned place preference in rats.

    PubMed

    Al Ameri, Mouza; Al Mansouri, Shamma; Al Maamari, Alyazia; Bahi, Amine

    2014-10-01

    Recent evidence suggests that epigenetic mechanisms such as chromatin modification (specifically histone acetylation) may play a crucial role in the development of addictive behavior. However, little is known about the role of epigenetic modifications in the rewarding properties of ethanol. In the current study, we studied the effects of systemic injection of the histone deacetylase (HDAC) inhibitor, valproic acid (VPA) on ethanol consumption and ethanol-elicited conditioned place preference (CPP). The effect of VPA (300 mg/kg) on voluntary ethanol intake and preference was assessed using continuous two-bottle choice procedure with escalating concentrations of alcohol (2.5-20% v/v escalating over 4 weeks). Taste sensitivity was studies using saccharin (sweet; 0.03% and 0.06%) and quinine (bitter; 20 µM and 40 µM) tastants solutions. Ethanol conditioned reward was investigated using an unbiased CPP model. Blood ethanol concentration (BEC) was also measured. Compared to vehicle, VPA-injected rats displayed significantly lower preference and consumption of ethanol in a two-bottle choice paradigm, with no significant difference observed with saccharin and quinine. More importantly, 0.5 g/kg ethanol-induced-CPP acquisition was blocked following VPA administration. Finally, vehicle- and VPA-treated mice had similar BECs. Taken together, our results implicated HDAC inhibition in the behavioral and reinforcement-related effects of alcohol and raise the question of whether specific drugs that target HDAC could potentially help to tackle alcoholism in humans. PMID:25108044

  5. Exploring inhibitor release pathways in histone deacetylases using random acceleration molecular dynamics simulations.

    PubMed

    Kalyaanamoorthy, Subha; Chen, Yi-Ping Phoebe

    2012-02-27

    Molecular channel exploration perseveres to be the prominent solution for eliciting structure and accessibility of active site and other internal spaces of macromolecules. The volume and silhouette characterization of these channels provides answers for the issues of substrate access and ligand swapping between the obscured active site and the exterior of the protein. Histone deacetylases (HDACs) are metal-dependent enzymes that are involved in the cell growth, cell cycle regulation, and progression, and their deregulations have been linked with different types of cancers. Hence HDACs, especially the class I family, are widely recognized as the important cancer targets, and the characterizations of their structures and functions have been of special interest in cancer drug discovery. The class I HDACs are known to possess two different protein channels, an 11 Å and a 14 Å (named channels A and B1, respectively), of which the former is a ligand or substrate occupying tunnel that leads to the buried active site zinc ion and the latter is speculated to be involved in product release. In this work, we have carried out random acceleration molecular dynamics (RAMD) simulations coupled with the classical molecular dynamics to explore the release of the ligand, N-(2-aminophenyl) benzamide (LLX) from the active sites of the recently solved X-ray crystal structure of HDAC2 and the computationally modeled HDAC1 proteins. The RAMD simulations identified significant structural and dynamic features of the HDAC channels, especially the key 'gate-keeping' amino acid residues that control these channels and the ligand release events. Further, this study identified a novel and unique channel B2, a subchannel from channel B1, in the HDAC1 protein structure. The roles of water molecules in the LLX release from the HDAC1 and HDAC2 enzymes are also discussed. Such structural and dynamic properties of the HDAC protein channels that govern the ligand escape reactions will provide

  6. HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment.

    PubMed

    Colussi, Claudia; Mozzetta, Chiara; Gurtner, Aymone; Illi, Barbara; Rosati, Jessica; Straino, Stefania; Ragone, Gianluca; Pescatori, Mario; Zaccagnini, Germana; Antonini, Annalisa; Minetti, Giulia; Martelli, Fabio; Piaggio, Giulia; Gallinari, Paola; Steinkuhler, Christian; Steinkulher, Christian; Clementi, Emilio; Dell'Aversana, Carmela; Altucci, Lucia; Mai, Antonello; Capogrossi, Maurizio C; Puri, Pier Lorenzo; Gaetano, Carlo

    2008-12-01

    The overlapping histological and biochemical features underlying the beneficial effect of deacetylase inhibitors and NO donors in dystrophic muscles suggest an unanticipated molecular link among dystrophin, NO signaling, and the histone deacetylases (HDACs). Higher global deacetylase activity and selective increased expression of the class I histone deacetylase HDAC2 were detected in muscles of dystrophin-deficient MDX mice. In vitro and in vivo siRNA-mediated down-regulation of HDAC2 in dystrophic muscles was sufficient to replicate the morphological and functional benefits observed with deacetylase inhibitors and NO donors. We found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation. These data reveal a special contribution of HDAC2 in the pathogenesis of Duchenne muscular dystrophy and indicate that HDAC2 inhibition by NO-dependent S-nitrosylation is important for the therapeutic response to NO donors in MDX mice. They also define a common target for independent pharmacological interventions in the treatment of Duchenne muscular dystrophy. PMID:19047631

  7. HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment

    PubMed Central

    Colussi, Claudia; Mozzetta, Chiara; Gurtner, Aymone; Illi, Barbara; Rosati, Jessica; Straino, Stefania; Ragone, Gianluca; Pescatori, Mario; Zaccagnini, Germana; Antonini, Annalisa; Minetti, Giulia; Martelli, Fabio; Piaggio, Giulia; Gallinari, Paola; Steinkuhler, Christian; Clementi, Emilio; Dell'Aversana, Carmela; Altucci, Lucia; Mai, Antonello; Capogrossi, Maurizio C.; Puri, Pier Lorenzo; Gaetano, Carlo

    2008-01-01

    The overlapping histological and biochemical features underlying the beneficial effect of deacetylase inhibitors and NO donors in dystrophic muscles suggest an unanticipated molecular link among dystrophin, NO signaling, and the histone deacetylases (HDACs). Higher global deacetylase activity and selective increased expression of the class I histone deacetylase HDAC2 were detected in muscles of dystrophin-deficient MDX mice. In vitro and in vivo siRNA-mediated down-regulation of HDAC2 in dystrophic muscles was sufficient to replicate the morphological and functional benefits observed with deacetylase inhibitors and NO donors. We found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation. These data reveal a special contribution of HDAC2 in the pathogenesis of Duchenne muscular dystrophy and indicate that HDAC2 inhibition by NO-dependent S-nitrosylation is important for the therapeutic response to NO donors in MDX mice. They also define a common target for independent pharmacological interventions in the treatment of Duchenne muscular dystrophy. PMID:19047631

  8. Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development.

    PubMed

    Lewandowski, Sara L; Janardhan, Harish P; Trivedi, Chinmay M

    2015-11-01

    About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the epigenome; however, their functions within the second heart field remain elusive. Here we demonstrate that histone deacetylase 3 (HDAC3) orchestrates epigenetic silencing of Tgf-β1, a causative factor in congenital heart disease pathogenesis, in a deacetylase-independent manner to regulate development of second heart field-derived structures. In murine embryos lacking HDAC3 in the second heart field, increased TGF-β1 bioavailability is associated with ascending aortic dilatation, outflow tract malrotation, overriding aorta, double outlet right ventricle, aberrant semilunar valve development, bicuspid aortic valve, ventricular septal defects, and embryonic lethality. Activation of TGF-β signaling causes aberrant endothelial-to-mesenchymal transition and altered extracellular matrix homeostasis in HDAC3-null outflow tracts and semilunar valves, and pharmacological inhibition of TGF-β rescues these defects. HDAC3 recruits components of the PRC2 complex, methyltransferase EZH2, EED, and SUZ12, to the NCOR complex to enrich trimethylation of Lys-27 on histone H3 at the Tgf-β1 regulatory region and thereby maintains epigenetic silencing of Tgf-β1 specifically within the second heart field-derived mesenchyme. Wild-type HDAC3 or catalytically inactive HDAC3 expression rescues aberrant endothelial-to-mesenchymal transition and epigenetic silencing of Tgf-β1 in HDAC3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the second heart field is a predisposing factor for congenital heart disease. PMID:26420484

  9. Dietary regulation of histone acetylases and deacetylases for the prevention of metabolic diseases.

    PubMed

    Pham, Tho X; Lee, Jiyoung

    2012-12-01

    Age-related diseases such as type 2 diabetes, cardiovascular disease, and cancer involve epigenetic modifications, where accumulation of minute changes in the epigenome over time leads to disease manifestation. Epigenetic changes are influenced by life style and diets. This represents an avenue whereby dietary components could accelerate or prevent age-related diseases through their effects on epigenetic modifications. Histone acetylation is an epigenetic modification that is regulated through the opposing action of histone acetylases (HATs) and deacetylases (HDACs). These two families of enzymes play critical roles in metabolic processes and their dysregulation is associated with pathogenesis of several diseases. Dietary components, such as butyrate, sulforaphane, and curcumin, have been shown to affect HAT and HDAC activity, and their health benefits are attributed, at least in part, to epigenetic modifications. Given the decades that it takes to accumulate epigenetic changes, it is unlikely that pharmaceuticals could undo epigenetic changes without side effects. Therefore, long term consumption of dietary components that can alter the epigenome could be an attractive means of disease prevention. The goal of this review is to highlight the roles of diets and food components in epigenetic modifications through the regulation of HATs and HDACs for disease prevention. PMID:23363995

  10. Regulation of C/EBPdelta-dependent transactivation by histone deacetylases in intestinal epithelial cells.

    PubMed

    Turgeon, Naomie; Valiquette, Caroline; Blais, Mylène; Routhier, Sophie; Seidman, Ernest G; Asselin, Claude

    2008-04-01

    The C/EBPdelta transcription factor is involved in the positive regulation of the intestinal epithelial cell acute phase response. C/EBPdelta regulation by histone deacetylases (HDACs) during the course of inflammation remains to be determined. Our aim was to examine the effect of HDACs on C/EBPdelta-dependent regulation of haptoglobin, an acute phase protein induced in intestinal epithelial cells in response to pro-inflammatory cytokines. HDAC1, HDAC3, and HDAC4 were expressed in intestinal epithelial cells, as determined by Western blot. GST pull-down assays showed specific HDAC1 interactions with the transcriptional activation and the b-ZIP C/EBPdelta domains, while the co-repressor mSin3A interacts with the C-terminal domain. Immunoprecipitation assays confirmed the interaction between HDAC1 and the N-terminal C/EBPdelta amino acid 36-164 domain. HDAC1 overexpression decreased C/EBPdelta transcriptional activity of the haptoglobin promoter, as assessed by transient transfection and luciferase assays. Chromatin immunoprecipitation analysis showed a displacement of HDAC1 from the haptoglobin promoter in response to inflammatory stimuli and an increased acetylation of histone H3 and H4. HDAC1 silencing by shRNA expression increased both basal and IL-1beta-induced haptoglobin mRNA levels in epithelial intestinal cells. Our results suggest that interactions between C/EBPs and HDAC1 negatively regulate C/EBPdelta-dependent haptoglobin expression in intestinal epithelial cells. PMID:17910034