Journal articles on the topic 'Epigenetics: histone deacetylase'
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1
Ružić, Dušan, Nemanja Đoković, Katarina Nikolić, and Zorica Vujić. "Medicinal chemistry of histone deacetylase inhibitors." Arhiv za farmaciju 71, no. 2 (2021): 73–100. http://dx.doi.org/10.5937/arhfarm71-30618.
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Today, we are witnessing an explosion of scientific concepts in cancer chemotherapy. It has been considered for a long time that genetic instability in cancer should be treated with drugs that directly damage the DNA. Understanding the molecular basis of malignant diseases shed light on studying phenotypic plasticity. In the era of epigenetics, many efforts are being made to alter the aberrant homeostasis in cancer without modifying the DNA sequence. One such strategy is modulation of the lysine acetylome in human cancers. To remove the acetyl group from the histones, cells use the enzymes that are called histone deacetylases (HDACs). The disturbed equilibrium between acetylation and deacetylation on lysine residues of histones can be manipulated with histone deacetylase inhibitors (HDACi). Throughout the review, an effort will be made to present the mechanistic basis of targeting the HDAC isoforms, discovered selective HDAC inhibitors, and their therapeutical implications and expectations in modern drug discovery.
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Licciardi, Paul V., and Tom C. Karagiannis. "Regulation of Immune Responses by Histone Deacetylase Inhibitors." ISRN Hematology 2012 (March 18, 2012): 1–10. http://dx.doi.org/10.5402/2012/690901.
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Both genetic and epigenetic factors are important regulators of the immune system. There is an increasing body of evidence attesting to epigenetic modifications that influence the development of distinct innate and adaptive immune response cells. Chromatin remodelling via acetylation, methylation, phosphorylation, and ubiquitination of histone proteins as well as DNA, methylation is epigenetic mechanisms by which immune gene expression can be controlled. In this paper, we will discuss the role of epigenetics in the regulation of host immunity, with particular emphasis on histone deacetylase inhibitors. In particular, the role of HDAC inhibitors as a new class of immunomodulatory therapeutics will also be reviewed.
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Ikeda, Yuka, Nozomi Nagase, Ai Tsuji, Kurumi Taniguchi, Yasuko Kitagishi, and Satoru Matsuda. "Comprehension of the Relationship between Autophagy and Reactive Oxygen Species for Superior Cancer Therapy with Histone Deacetylase Inhibitors." Oxygen 1, no. 1 (July 25, 2021): 22–31. http://dx.doi.org/10.3390/oxygen1010004.
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Epigenetics contains various mechanisms by which cells employ to regulate the transcription of many DNAs. Histone acetylation is an obvious example of the epigenetic mechanism regulating the expression of several genes by changing chromatin accessibility. Histone deacetylases (HDACs) are a class of enzymes that play a critical role in the epigenetic regulation by deacetylation of histone proteins. Inhibitors of the histone deacetylase could result in hyperacetylation of histones, which eventually induce various cellular consequences such as generation of reactive oxygen species (ROS), activation of apoptotic pathways, and initiating autophagy. In particular, excessive levels of ROS have been proposed to contribute to the pathophysiology of various diseases including cancer. Cancers are, as it were, a class of redox diseases. Low levels of ROS are beneficial for cells, however, cancer cells generally have high levels of ROS, which makes them more susceptible than normal cells to the further increases of ROS levels. Cancer cells exhibit metabolic alterations for managing to sustain these oxidative stresses. There is a growing interest in the use of HDAC inhibitors as promising cancer therapeutics with potentiating the activity of established therapeutic applications. Therefore, it should be important to understand the underlying relationship between the regulation of HDACs, ROS production, and cancer cell biology.
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Hassell. "Histone Deacetylases and their Inhibitors in Cancer Epigenetics." Diseases 7, no. 4 (November 1, 2019): 57. http://dx.doi.org/10.3390/diseases7040057.
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Histone deacetylases (HDAC) and histone deacetylase inhibitors (HDACi) have greatly impacted the war on cancer. Their role in epigenetics has significantly altered the development of anticancer drugs used to treat the most rare, persistent forms of cancer. During transcription, HDAC and HDACi are used to regulate the genetic mutations found in cancerous cells by removing and/or preventing the removal of the acetyl group on specific histones. This activity determines the relaxed or condensed conformation of the nucleosome, changing the accessibility zones for transcription factors. These modifications lead to other biological processes for the cell, including cell cycle progression, proliferation, and differentiation. Each HDAC and HDACi class or group has a distinctive mechanism of action that can be utilized to halt the progression of cancerous cell growth. While the use of HDAC- and HDACi-derived compounds are relatively new in treatment of cancers, they have a proven efficacy when the appropriately utilized. This following manuscript highlights the mechanisms of action utilized by HDAC and HDACi in various cancer, their role in epigenetics, current drug manufacturers, and the impact predicative modeling systems have on cancer therapeutic drug discovery.
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Peng, Xiaopeng, Guochao Liao, Pinghua Sun, Zhiqiang Yu, and Jianjun Chen. "An Overview of HDAC Inhibitors and their Synthetic Routes." Current Topics in Medicinal Chemistry 19, no. 12 (July 30, 2019): 1005–40. http://dx.doi.org/10.2174/1568026619666190227221507.
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Epigenetics play a key role in the origin, development and metastasis of cancer. Epigenetic processes include DNA methylation, histone acetylation, histone methylation, and histone phosphorylation, among which, histone acetylation is the most common one that plays important roles in the regulation of normal cellular processes, and is controlled by histone deacetylases (HDACs) and histone acetyltransferases (HATs). HDACs are involved in the regulation of many key cellular processes, such as DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function, and can lead to oncogene activation. As a result, HDACs are considered to be an excellent target for anti-cancer therapeutics like histone deacetylase inhibitors (HDACi) which have attracted much attention in the last decade. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. The primary purpose of this paper is to summarize recent HDAC inhibitors and the synthetic routes as well as to discuss the direction for the future development of new HDAC inhibitors.
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Drożak, Paulina, Łukasz Bryliński, and Joanna Zawitkowska. "A Comprehensive Overview of Recent Advances in Epigenetics in Pediatric Acute Lymphoblastic Leukemia." Cancers 14, no. 21 (November 1, 2022): 5384. http://dx.doi.org/10.3390/cancers14215384.
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Recent years have brought a novel insight into our understanding of childhood acute lymphoblastic leukemia (ALL), along with several breakthrough treatment methods. However, multiple aspects of mechanisms behind this disease remain to be elucidated. Evidence suggests that leukemogenesis in ALL is widely influenced by epigenetic modifications. These changes include: DNA hypermethylation, histone modification and miRNA alteration. DNA hypermethylation in promoter regions, which leads to silencing of tumor suppressor genes, is a common epigenetic alteration in ALL. Histone modifications are mainly caused by an increased expression of histone deacetylases. A dysregulation of miRNA results in changes in the expression of their target genes. To date, several hundred genes were identified as suppressed by epigenetic mechanisms in ALL. What is promising is that epigenetic alterations in ALL may be used as potential biomarkers for classification of subtypes, predicting relapse and disease progression and assessing minimal residual disease. Furthermore, since epigenetic lesions are potentially reversible, an activation of epigenetically silenced genes with the use of hypomethylating agents or histone deacetylase inhibitors may be utilized as a therapeutic strategy for ALL. The following review summarizes our current knowledge about epigenetic modifications in ALL and describes potential uses of epigenetics in the clinical management of this disease.
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Amarante, Anderson de Mendonça, Isabel Caetano de Abreu da Silva, Vitor Coutinho Carneiro, Amanda Roberta Revoredo Vicentino, Marcia de Amorim Pinto, Luiza Mendonça Higa, Kanhu Charan Moharana, et al. "Zika virus infection drives epigenetic modulation of immunity by the histone acetyltransferase CBP of Aedes aegypti." PLOS Neglected Tropical Diseases 16, no. 6 (June 27, 2022): e0010559. http://dx.doi.org/10.1371/journal.pntd.0010559.
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Epigenetic mechanisms are responsible for a wide range of biological phenomena in insects, controlling embryonic development, growth, aging and nutrition. Despite this, the role of epigenetics in shaping insect-pathogen interactions has received little attention. Gene expression in eukaryotes is regulated by histone acetylation/deacetylation, an epigenetic process mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, we explored the role of the Aedes aegypti histone acetyltransferase CBP (AaCBP) after infection with Zika virus (ZIKV), focusing on the two main immune tissues, the midgut and fat body. We showed that the expression and activity of AaCBP could be positively modulated by blood meal and ZIKV infection. Nevertheless, Zika-infected mosquitoes that were silenced for AaCBP revealed a significant reduction in the acetylation of H3K27 (CBP target marker), followed by downmodulation of the expression of immune genes, higher titers of ZIKV and lower survival rates. Importantly, in Zika-infected mosquitoes that were treated with sodium butyrate, a histone deacetylase inhibitor, their capacity to fight virus infection was rescued. Our data point to a direct correlation among histone hyperacetylation by AaCBP, upregulation of antimicrobial peptide genes and increased survival of Zika-infected-A. aegypti.
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Santana, Dalileia Aparecida, Marilia de Arruda Cardoso Smith, and Elizabeth Suchi Chen. "Histone Modifications in Alzheimer’s Disease." Genes 14, no. 2 (January 29, 2023): 347. http://dx.doi.org/10.3390/genes14020347.
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Since Late-onset Alzheimer’s disease (LOAD) derives from a combination of genetic variants and environmental factors, epigenetic modifications have been predicted to play a role in the etiopathology of LOAD. Along with DNA methylation, histone modifications have been proposed as the main epigenetic modifications that contribute to the pathologic mechanisms of LOAD; however, little is known about how these mechanisms contribute to the disease’s onset or progression. In this review, we highlighted the main histone modifications and their functional role, including histone acetylation, histone methylation, and histone phosphorylation, as well as changes in such histone modifications that occur in the aging process and mainly in Alzheimer’s disease (AD). Furthermore, we pointed out the main epigenetic drugs tested for AD treatment, such as those based on histone deacetylase (HDAC) inhibitors. Finally, we remarked on the perspectives around the use of such epigenetics drugs for treating AD.
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Saco, Tara V., Prasanna Tamarapu Parthasarathy, Young Cho, Richard F. Lockey, and Narasaiah Kolliputi. "Role of epigenetics in pulmonary hypertension." American Journal of Physiology-Cell Physiology 306, no. 12 (June 15, 2014): C1101—C1105. http://dx.doi.org/10.1152/ajpcell.00314.2013.
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A significant amount of research has been conducted to examine the pathologic processes and epigenetic mechanisms contributing to peripheral hypertension. However, few studies have been carried out to understand the vascular remodeling behind pulmonary hypertension (PH), including peripheral artery muscularization, medial hypertrophy and neointima formation in proximal arteries, and plexiform lesion formation. Similarly, research examining some of the epigenetic principles that may contribute to this vascular remodeling, such as DNA methylation and histone modification, is minimal. The understanding of these principles may be the key to developing new and more effective treatments for PH. The purpose of this review is to summarize epigenetic research conducted in the field of hypertension that could possibly be used to understand the epigenetics of PH. Possible future therapies that could be pursued using information from these studies include selective histone deacetylase inhibitors and targeted DNA methyltransferases. Both of these could potentially be used to silence proproliferative or antiapoptotic genes that lead to decreased smooth muscle cell proliferation. Epigenetics may provide a glimmer of hope for the eventual improved treatment of this highly morbid and debilitating disease.
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Stintzing, Sebastian, Ralf Kemmerling, Tobias Kiesslich, Beate Alinger, Matthias Ocker, and Daniel Neureiter. "Myelodysplastic Syndrome and Histone Deacetylase Inhibitors: “To Be or Not to Be Acetylated”?" Journal of Biomedicine and Biotechnology 2011 (2011): 1–15. http://dx.doi.org/10.1155/2011/214143.
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Myelodysplastic syndrome (MDS) represents a heterogeneous group of diseases with clonal proliferation, bone marrow failure and increasing risk of transformation into an acute myeloid leukaemia. Structured guidelines are developed for selective therapy based on prognostic subgroups, age, and performance status. Although many driving forces of disease phenotype and biology are described, the complete and possibly interacting pathogenetic pathways still remain unclear. Epigenetic investigations of cancer and haematologic diseases like MDS give new insights into the pathogenesis of this complex disease. Modifications of DNA or histones via methylation or acetylation lead to gene silencing and altered physiology relevant for MDS. First clinical trials give evidence that patients with MDS could benefit from epigenetic treatment with, for example, DNA methyl transferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi). Nevertheless, many issues of HDACi remain incompletely understood and pose clinical and translational challenges. In this paper, major aspects of MDS, MDS-associated epigenetics and the potential use of HDACi are discussed.
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Abdullah, Omeima, and Mahmoud Alhosin. "HAUSP Is a Key Epigenetic Regulator of the Chromatin Effector Proteins." Genes 13, no. 1 (December 24, 2021): 42. http://dx.doi.org/10.3390/genes13010042.
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HAUSP (herpes virus-associated ubiquitin-specific protease), also known as Ubiquitin Specific Protease 7, plays critical roles in cellular processes, such as chromatin biology and epigenetics, through the regulation of different signaling pathways. HAUSP is a main partner of the “Epigenetic Code Replication Machinery,” ECREM, a large protein complex that includes several epigenetic players, such as the ubiquitin-like containing plant homeodomain (PHD) and an interesting new gene (RING), finger domains 1 (UHRF1), as well as DNA methyltransferase 1 (DNMT1), histone deacetylase 1 (HDAC1), histone methyltransferase G9a, and histone acetyltransferase TIP60. Due to its deubiquitinase activity and its ability to team up through direct interactions with several epigenetic regulators, mainly UHRF1, DNMT1, TIP60, the histone lysine methyltransferase EZH2, and the lysine-specific histone demethylase LSD1, HAUSP positions itself at the top of the regulatory hierarchies involved in epigenetic silencing of tumor suppressor genes in cancer. This review highlights the increasing role of HAUSP as an epigenetic master regulator that governs a set of epigenetic players involved in both the maintenance of DNA methylation and histone post-translational modifications.
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Karpenko, D. V., N. A. Petinati, N. J. Drize, and A. E. Bigildeev. "The Role of epigenetic modifications of DNA and histones in the treatment of oncohematological diseases." Russian journal of hematology and transfusiology 66, no. 2 (September 2, 2021): 263–79. http://dx.doi.org/10.35754/0234-5730-2021-66-2-263-279.
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Introduction. Current knowledge of tumour biology attests a dual genetic and epigenetic nature of cancer cell abnormalities. Tumour epigenetics research provided insights into the key pathways mediating oncogenesis and facilitated novel epigenetic therapies.Aim — an overview of intricate involvement of epigenetic change in haematological morbidity and current therapeutic approaches to target the related mechanisms.Main findings. We review the best known epigenetic marks in tumour cells, e.g. DNA cytosine methylation, methylation and acetylation of histone proteins, the underlying enzymatic machinery and its role in oncogenesis. The epigenetic profile-changing drugs are described, including DNA hypomethylating agents, histone deacetylase and methylase inhibitors. A particular focus is made on substances currently approved in haematological therapy or undergoing clinical trial phases for future clinical availability.
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Číž, Milan, Adéla Dvořáková, Veronika Skočková, and Lukáš Kubala. "The Role of Dietary Phenolic Compounds in Epigenetic Modulation Involved in Inflammatory Processes." Antioxidants 9, no. 8 (August 3, 2020): 691. http://dx.doi.org/10.3390/antiox9080691.
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A better understanding of the interactions between dietary phenolic compounds and the epigenetics of inflammation may impact pathological conditions and their treatment. Phenolic compounds are well-known for their antioxidant, anti-inflammatory, anti-angiogenic, and anti-cancer properties, with potential benefits in the treatment of various human diseases. Emerging studies bring evidence that nutrition may play an essential role in immune system modulation also by altering gene expression. This review discusses epigenetic mechanisms such as DNA methylation, post-translational histone modification, and non-coding microRNA activity that regulate the gene expression of molecules involved in inflammatory processes. Special attention is paid to the molecular basis of NF-κB modulation by dietary phenolic compounds. The regulation of histone acetyltransferase and histone deacetylase activity, which all influence NF-κB signaling, seems to be a crucial mechanism of the epigenetic control of inflammation by phenolic compounds. Moreover, chronic inflammatory processes are reported to be closely connected to the major stages of carcinogenesis and other non-communicable diseases. Therefore, dietary phenolic compounds-targeted epigenetics is becoming an attractive approach for disease prevention and intervention.
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Juergens, Rosalyn A., and Charles M. Rudin. "Aberrant Epigenetic Regulation: A Central Contributor to Lung Carcinogenesis and a New Therapeutic Target." American Society of Clinical Oncology Educational Book, no. 33 (May 2013): e295-e300. http://dx.doi.org/10.14694/edbook_am.2013.33.e295.
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Carcinogenesis is driven by a combination of genetic and epigenetic abnormalities. Aberrancies in gene promoter methylation patterns and histone acetylation are associated with silencing of tumor suppressor genes in lung cancer and other solid tumors. Identification of key epigenetic modifications has been shown to be prognostic in early-stage non-small cell lung cancer. Previous clinical trials aimed at modifying the epigenome with single-agent demethylating agents or histone deacetylase inhibitors given at maximally tolerated doses have provided disappointing results. A recent clinical trial using a combination of a demethylating agent and a histone deacetylase inhibitor at “epigenetically targeted” doses concomitantly has shown promising results, including a patient with a complete objective response. Biomarkers associated with this clinical trial suggest that patients who undergo robust demethylation, as detected in the peripheral blood after a month on treatment, identifies those who gain the most benefit from this novel treatment strategy. Based on observations of unusually durable responses to subsequent therapy after administration of combined epigenetic therapy, epigenetic therapy may also play a role in “priming” patients to better respond to standard cytotoxic therapy or immunotherapy. This manuscript will review the data on the role of epigenetics in lung cancer and the history of epigenetic treatments in lung cancer spanning over the last 40 years.
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Moore, Spencer M., and John B. Christoforidis. "Advances in Ophthalmic Epigenetics and Implications for Epigenetic Therapies: A Review." Genes 14, no. 2 (February 5, 2023): 417. http://dx.doi.org/10.3390/genes14020417.
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The epigenome represents a vast molecular apparatus that writes, reads, and erases chemical modifications to the DNA and histone code without changing the DNA base-pair sequence itself. Recent advances in molecular sequencing technology have revealed that epigenetic chromatin marks directly mediate critical events in retinal development, aging, and degeneration. Epigenetic signaling regulates retinal progenitor (RPC) cell cycle exit during retinal laminar development, giving rise to retinal ganglion cells (RGCs), amacrine cells, horizontal cells, bipolar cells, photoreceptors, and Müller glia. Age-related epigenetic changes such as DNA methylation in the retina and optic nerve are accelerated in pathogenic conditions such as glaucoma and macular degeneration, but reversing these epigenetic marks may represent a novel therapeutic target. Epigenetic writers also integrate environmental signals such as hypoxia, inflammation, and hyperglycemia in complex retinal conditions such as diabetic retinopathy (DR) and choroidal neovascularization (CNV). Histone deacetylase (HDAC) inhibitors protect against apoptosis and photoreceptor degeneration in animal models of retinitis pigmentosa (RP). The epigenome represents an intriguing therapeutic target for age-, genetic-, and neovascular-related retinal diseases, though more work is needed before advancement to clinical trials.
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Zhang, Yuchen, Dhanusha A. Nalawansha, Kavinda E. Herath, Rafael Andrade, and Mary Kay H. Pflum. "Differential profiles of HDAC1 substrates and associated proteins in breast cancer cells revealed by trapping." Molecular Omics 17, no. 4 (2021): 544–53. http://dx.doi.org/10.1039/d0mo00047g.
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The substrates and associated proteins of histone deacetylase 1 (HDAC1) were profiled in triple negative breast cancers using mutant trapping for the first time to document the variable roles of HDAC1 in epigenetics and other cellular processes.
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Mummery, A., A. Narendran, and K. Y. Lee. "Targeting Epigenetics through Histone Deacetylase Inhibitors in Acute Lymphoblastic Leukemia." Current Cancer Drug Targets 11, no. 7 (September 1, 2011): 882–93. http://dx.doi.org/10.2174/156800911796798922.
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Yao, Hongwei, and Irfan Rahman. "Role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and COPD." American Journal of Physiology-Lung Cellular and Molecular Physiology 303, no. 7 (October 1, 2012): L557—L566. http://dx.doi.org/10.1152/ajplung.00175.2012.
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Histone deacetylase 2 (HDAC2) is a class I histone deacetylase that regulates various cellular processes, such as cell cycle, senescence, proliferation, differentiation, development, apoptosis, and glucocorticoid function in inhibiting inflammatory response. HDAC2 has been shown to protect against DNA damage response and cellular senescence/premature aging via an epigenetic mechanism in response to oxidative stress. These phenomena are observed in patients with chronic obstructive pulmonary disease (COPD). HDAC2 is posttranslationally modified by oxidative/carbonyl stress imposed by cigarette smoke and oxidants, leading to its reduction via an ubiquitination-proteasome dependent degradation in lungs of patients with COPD. In this perspective, we have discussed the role of HDAC2 posttranslational modifications and its role in regulation of inflammation, histone/DNA epigenetic modifications, DNA damage response, and cellular senescence, particularly in inflammaging, and during the development of COPD. We have also discussed the potential directions for future translational research avenues in modulating lung inflammaging and cellular senescence based on epigenetic chromatin modifications in diseases associated with increased oxidative stress.
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Claveria-Cabello, Alex, Leticia Colyn, Maria Arechederra, Jesus M. Urman, Carmen Berasain, Matias A. Avila, and Maite G. Fernandez-Barrena. "Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?" Cells 9, no. 10 (October 19, 2020): 2321. http://dx.doi.org/10.3390/cells9102321.
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Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis.
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Bai, Yu, Daid Ahmad, Ting Wang, Guihua Cui, and Wenliang Li. "Research Advances in the Use of Histone Deacetylase Inhibitors for Epigenetic Targeting of Cancer." Current Topics in Medicinal Chemistry 19, no. 12 (July 30, 2019): 995–1004. http://dx.doi.org/10.2174/1568026619666190125145110.
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The causes and progression of cancer are controlled by epigenetic processes. The mechanisms involved in epigenetic regulation of cancer development, gene expression, and signaling pathways have been studied. Histone deacetylases (HDACs) have a major impact on chromatin remodeling and epigenetics, making their inhibitors a very interesting area of cancer research. This review comprehensively summarizes the literature regarding HDAC inhibitors (HDACis) as an anticancer treatment published in the past few years. In addition, we explain the mechanisms of their therapeutic effects on cancer. An analysis of the beneficial characteristics and drawbacks of HDACis also is presented, which will assist preclinical and clinical researchers in the design of future experiments to improve the therapeutic efficacy of these drugs and circumvent the challenges in the path of successful epigenetic therapy. Future therapeutic strategies may include a combination of HDACis and chemotherapy or other inhibitors to target multiple oncogenic signaling pathways.
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Hara, Natsumi, and Yu Sawada. "Epigenetics of Cutaneous T-Cell Lymphomas." International Journal of Molecular Sciences 23, no. 7 (March 24, 2022): 3538. http://dx.doi.org/10.3390/ijms23073538.
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Epigenetic modifications rarely occur in isolation (as single “epigenetic modifications”). They usually appear together and form a network to control the epigenetic system. Cutaneous malignancies are usually affected by epigenetic changes. However, there is limited knowledge regarding the epigenetic changes associated with cutaneous lymphomas. In this review, we focused on cutaneous T-cell lymphomas such as mycosis fungoides, Sézary syndrome, and anaplastic large cell lymphoma. With regard to epigenetic changes, we summarize the detailed chemical modifications categorized into DNA methylation and histone acetylation and methylation. We also summarize the epigenetic modifications and characteristics of the drug for cutaneous T-cell lymphoma (CTCL). Furthermore, we discuss current research on epigenetic-targeted therapy against cutaneous T-cell lymphomas. Although the current method of treatment with histone deacetylase inhibitors does not exhibit sufficient therapeutic benefits in all cases of CTCL, epigenetic-targeted combination therapy might overcome this limitation for patients with CTCL.
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Schweizer, Sophie, Andreas Meisel, and Stefanie Märschenz. "Epigenetic Mechanisms in Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 33, no. 9 (June 12, 2013): 1335–46. http://dx.doi.org/10.1038/jcbfm.2013.93.
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Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration.
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Mostoslavsky, Raul. "Linking Epigenetics, Metabolism and Cancer: Lessons From SIRT6." Innovation in Aging 4, Supplement_1 (December 1, 2020): 741. http://dx.doi.org/10.1093/geroni/igaa057.2651.
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Abstract In recent years, chromatin regulators have emerged as key modulators in cancer. We discovered that the mammalian histone deacetylase SIRT6 is a key chromatin factor, modulating expression of metabolic, developmental, and ribosomal protein genes. In recent studies, we identified a loss of function mutation in SIRT6 behind a human syndrome of perinatal lethality. In the context of cancer, we found SIRT6 to act as a robust tumor suppressor, by modulating glucose metabolism. As Otto Warburg described decades ago, cancer cells exhibit glycolytic metabolism, where pyruvate, instead of contributing to ATP production in the mitochondria, is converted to lactate even under normoxia conditions. We found SIRT6 as the first chromatin factor in charge of suppressing the Warburg effect in colon and skin cancer. At the cellular level, SIRT6 inactivation leads to increased cellular glucose uptake, higher lactate production and decreased mitochondrial activity. Our results indicate that SIRT6 directly regulates expression of several key glycolytic and ribosomal genes, co-repressing Hif1a and Myc, respectively, and acting as a histone H3 lysine9 (H3K9) and lysine 56 (H3K56) deacetylase. Notably, we recently identified SIRT6 as the first deacetylase to specifically inhibit transcriptional elongation, rather than initiation, in its targets. Strikingly, we determined in new studies that such glycolytic switch provides an advantage even at the early initiating cancer stem cells stage, in what we identified as the cell-of-origin for the Warburg effect. In addition, we found SIRT6 to act as a robust tumor suppressor in the context of pancreatic cancer. However, in this case, SIRT6 did not influence metabolism, but rather silenced expression of the developmental gene Lin28b, in this way protecting against aggressive undifferentiated pancreatic adenocarcinoma. Our studies highlight the important role epigenetic factors, such as SIRT6, play in protecting against tumor progression by providing “epigenetic plasticity”, inhibiting adaptive responses in transformed cells.
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Rump, Katharina, and Michael Adamzik. "Epigenetic Mechanisms of Postoperative Cognitive Impairment Induced by Anesthesia and Neuroinflammation." Cells 11, no. 19 (September 21, 2022): 2954. http://dx.doi.org/10.3390/cells11192954.
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Cognitive impairment after surgery is a common problem, affects mainly the elderly, and can be divided into postoperative delirium and postoperative cognitive dysfunction. Both phenomena are accompanied by neuroinflammation; however, the precise molecular mechanisms underlying cognitive impairment after anesthesia are not yet fully understood. Anesthesiological drugs can have a longer-term influence on protein transcription, thus, epigenetics is a possible mechanism that impacts on cognitive function. Epigenetic mechanisms may be responsible for long-lasting effects and may implicate novel therapeutic approaches. Hence, we here summarize the existing literature connecting postoperative cognitive impairment to anesthesia. It becomes clear that anesthetics alter the expression of DNA and histone modifying enzymes, which, in turn, affect epigenetic markers, such as methylation, histone acetylation and histone methylation on inflammatory genes (e.g., TNF-alpha, IL-6 or IL1 beta) and genes which are responsible for neuronal development (such as brain-derived neurotrophic factor). Neuroinflammation is generally increased after anesthesia and neuronal growth decreased. All these changes can induce cognitive impairment. The inhibition of histone deacetylase especially alleviates cognitive impairment after surgery and might be a novel therapeutic option for treatment. However, further research with human subjects is necessary because most findings are from animal models.
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Etchegaray, Jean-Pierre, Lei Zhong, and Raul Mostoslavsky. "The Histone Deacetylase SIRT6: At the Crossroads Between Epigenetics, Metabolism and Disease." Current Topics in Medicinal Chemistry 13, no. 23 (December 3, 2013): 2991–3000. http://dx.doi.org/10.2174/15680266113136660213.
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Asaba, Yutaro, Shoichiro Asayama, and Hiroyoshi Kawakami. "Design of epigenetics control carrier for simultaneous transfection of histone acetyltransferase with histone deacetylase inhibitor to continuous histone acetylation." Polymer Journal 48, no. 5 (January 27, 2016): 561–64. http://dx.doi.org/10.1038/pj.2015.129.
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Man, Kenny, Liam Lawlor, Lin-Hua Jiang, and Xuebin B. Yang. "The Selective Histone Deacetylase Inhibitor MI192 Enhances the Osteogenic Differentiation Efficacy of Human Dental Pulp Stromal Cells." International Journal of Molecular Sciences 22, no. 10 (May 14, 2021): 5224. http://dx.doi.org/10.3390/ijms22105224.
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The use of human dental pulp stromal cells (hDPSCs) has gained increasing attention as an alternative stem cell source for bone tissue engineering. The modification of the cells’ epigenetics has been found to play an important role in regulating differentiation, with the inhibition of histone deacetylases 3 (HDAC3) being linked to increased osteogenic differentiation. This study aimed to induce epigenetic reprogramming using the HDAC2 and 3 selective inhibitor, MI192 to promote hDPSCs osteogenic capacity for bone regeneration. MI192 treatment caused a time–dose-dependent change in hDPSC morphology and reduction in viability. Additionally, MI192 successfully augmented hDPSC epigenetic functionality, which resulted in increased histone acetylation and cell cycle arrest at the G2/M phase. MI192 pre-treatment exhibited a dose-dependent effect on hDPSCs alkaline phosphatase activity. Quantitative PCR and In-Cell Western further demonstrated that MI192 pre-treatment significantly upregulated hDPSCs osteoblast-related gene and protein expression (alkaline phosphatase, bone morphogenic protein 2, type I collagen and osteocalcin) during osteogenic differentiation. Importantly, MI192 pre-treatment significantly increased hDPSCs extracellular matrix collagen production and mineralisation. As such, for the first time, our findings show that epigenetic reprogramming with the HDAC2 and 3 selective inhibitor MI192 accelerates the osteogenic differentiation of hDPSCs, demonstrating the considerable utility of this MSCs engineering approach for bone augmentation strategies.
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Morey, Lluis, Carmen Brenner, Francesco Fazi, Raffaella Villa, Arantxa Gutierrez, Marcus Buschbeck, Clara Nervi, Saverio Minucci, Francois Fuks, and Luciano Di Croce. "MBD3, a Component of the NuRD Complex, Facilitates Chromatin Alteration and Deposition of Epigenetic Marks." Molecular and Cellular Biology 28, no. 19 (July 21, 2008): 5912–23. http://dx.doi.org/10.1128/mcb.00467-08.
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ABSTRACT In plants, as in mammals, mutations in SNF2-like DNA helicases/ATPases were shown to affect not only chromatin structure but also global methylation patterns, suggesting a potential functional link between chromatin structure and epigenetic marks. The SNF2-like ATPase containing nucleosome remodeling and deacetylase corepressor complex (NuRD) is involved in gene transcriptional repression and chromatin remodeling. We have previously shown that the leukemogenic protein PML-RARa represses target genes through recruitment of DNA methytransferases and Polycomb complex. Here, we demonstrate a direct role of the NuRD complex in aberrant gene repression and transmission of epigenetic repressive marks in acute promyelocytic leukemia (APL). We show that PML-RARa binds and recruits NuRD to target genes, including to the tumor-suppressor gene RARβ2. In turn, the NuRD complex facilitates Polycomb binding and histone methylation at lysine 27. Retinoic acid treatment, which is often used for patients at the early phase of the disease, reduced the promoter occupancy of the NuRD complex. Knockdown of the NuRD complex in leukemic cells not only prevented histone deacetylation and chromatin compaction but also impaired DNA and histone methylation, as well as stable silencing, thus favoring cellular differentiation. These results unveil an important role for NuRD in the establishment of altered epigenetic marks in APL, demonstrating an essential link between chromatin structure and epigenetics in leukemogenesis that could be exploited for therapeutic intervention.
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Saksouk, Nehmé, Micah M. Bhatti, Sylvie Kieffer, Aaron T. Smith, Karine Musset, Jérôme Garin, William J. Sullivan, Marie-France Cesbron-Delauw, and Mohamed-Ali Hakimi. "Histone-Modifying Complexes Regulate Gene Expression Pertinent to the Differentiation of the Protozoan Parasite Toxoplasma gondii." Molecular and Cellular Biology 25, no. 23 (December 1, 2005): 10301–14. http://dx.doi.org/10.1128/mcb.25.23.10301-10314.2005.
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ABSTRACT Pathogenic apicomplexan parasites like Toxoplasma and Plasmodium (malaria) have complex life cycles consisting of multiple stages. The ability to differentiate from one stage to another requires dramatic transcriptional changes, yet there is a paucity of transcription factors in these protozoa. In contrast, we show here that Toxoplasma possesses extensive chromatin remodeling machinery that modulates gene expression relevant to differentiation. We find that, as in other eukaryotes, histone acetylation and arginine methylation are marks of gene activation in Toxoplasma. We have identified mediators of these histone modifications, as well as a histone deacetylase (HDAC), and correlate their presence at target promoters in a stage-specific manner. We purified the first HDAC complex from apicomplexans, which contains novel components in addition to others previously reported in eukaryotes. A Toxoplasma orthologue of the arginine methyltransferase CARM1 appears to work in concert with the acetylase TgGCN5, which exhibits an unusual bias for H3 [K18] in vitro. Inhibition of TgCARM1 induces differentiation, showing that the parasite life cycle can be manipulated by interfering with epigenetic machinery. This may lead to new approaches for therapy against protozoal diseases and highlights Toxoplasma as an informative model to study the evolution of epigenetics in eukaryotic cells.
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Selene, Insija Ilyas, Jemin Aby Jose, Muhammad Sardar, Zunairah Shah, Madeeha Shafqat, Warda Faridi, Mustafa Nadeem Malik, et al. "Histone Deacetylase Inhibitors in Myelodysplastic Syndrome." Blood 132, Supplement 1 (November 29, 2018): 5528. http://dx.doi.org/10.1182/blood-2018-99-119728.
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Abstract Background Myelodysplastic Syndrome (MDS) represents a heterogeneous group of diseases with clonal proliferation, bone marrow failure and increase risk of progression to acute leukemia. Histone deacetylase inhibitors (HDACi) modulate the epigenetics of cancer cells to promote differentiation and programmed cell death. Our aim is to study the efficacy and safety of HDACi in patients with MDS/ acute myeloid leukemia (AML). HDACi can be a safer alternative in patients with high risk MDS who are not eligible for stem cell transplantation or high intensity chemotherapy. Methods A comprehensive literature search was done using following 5 databases: (Pubmed,Embase,Web of Science,Cochrane library,Clinical Trials.Gov) in accordance with the PRISMA guidelines. We included 21 trials (Phase II/III ) with a total 1654 patients,of which 1030 patients recieved HDACi and were evaluable for respone. Our primary objective was to determine efficacy of HDACi based regimen in terms of overall response rate (ORR) and composite complete response rate (CCR). A meta-analysis was done for regimen that were evaluated in more than one trials to report ORR and CRR.CMA software V.3 was used to run metaanalysis to calculate the response and the heterogenity among studies were assesed by using I2 test.A random -effect model was applied. Results: The pooled analysis (95% CI) with 1030 evaluable patients in MDS/ AML showed an overall response rate of 37.1% (32.3-42.3 : I2= 86.105 )with composite response (comp CR=CR+Cri+mCR) of 30.8%(26.8-35.1) .The median overall survival of those who received HDACi ranges from 8 -25 months.The Base line Characterstics,Outcome and Toxicity of HDACi in MDS/AML are summarized in Table 1. In the meta-analysis (n=57) of two trials (Garcia et al, 2007 & Luger et al. 2013), combination regimen of Mocetinostat- Azacytidine had an ORR of 54%(95% CI: 10.2-92.3) and composite complete response (CCR) of 18.9% (95% CI :9.3-34.7) in patients with MDS/AML. Combination of Vorinostat-Cytarabine-Idarubicin had an ORR of 50.7% (95% CI :40.7-96.5) and CCR of 30.1% (95% CI: in 111 patients with MDS/AML in a meta-analysis of trials by Prebet et al. 2013 and Manero et al. 2012. The meta-analysis of 3 trials evaluating Vorinostat-Azacitadine regimen (Craddock et al. 2017; Sekers et al. 2017 & Montalbano et al. 2016) had an ORR 38.3%( 95 % CI :18-63) CCR of 29%(95% CI: 11-58) in a total patient population of 274 patients. The regimen of Valproate- Deictibine/Cytarabine was evaluated in 3 separate trials with a total patient population of 156 which showed an ORR of 41.6% (95 % CI :20.9-65.6)and a CCR of 28.3%(95% CI 18.9-42.7) in the metanalysis. The meta-analysis of 3 trials evaluating a three-drug regimen of Valproate-Azacytadine-All trans retinoic acid(ATRA) showed an ORR of 32.2%(95% CI :24.2-41.3) and CCR of 23.7%(95 %CI 13.1-39.0) in 144 MDS/AML patients. In a trial by Manero et al (2017), the combination of Pracinostat and Azacitadine had an ORR of 67.5% (95% CI :51.7-80.01) CCR of 60%(95% CI 44.3-73.8) in 51 AML/MDS patients. A single trial evaluating regimen of Panobinostat and Azacitadine (n=40) had an ORR of 37.5% and CCR of 27.5%. Combination of Panobinostat and Decitabine in a trial by Geoffry et al in 2017 (n=52), the ORR was 21.2% and CCR of 19.2%.The Overall response rate and Composite response rate of HDACi in MDS/AML are mentioned in Table 2 and Table 3. Conclusion: Most of the HDACi like Mocetinostat,Valproic acid ,Pracinostat when used in combination with either Hypomethylating agents(Azacytidine ,decitabine) or purine analogs (cytarabine/idarubicin) produced a good response.Pracinostat in combination with azacytidine showed the best ORR among the studies but there was only single study mentioning this combination.Single agent studies with resposne were also not evaluable.Most of MDS patients get resistant to hypomethlating agent thus there is need to explore newer agents and HDACi agents is a promising group. Disclosures No relevant conflicts of interest to declare.
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Wu, Yuan Seng, Zhong Yang Lee, Lay-Hong Chuah, Chun Wai Mai, and Siew Ching Ngai. "Epigenetics in Metastatic Breast Cancer: Its Regulation and Implications in Diagnosis, Prognosis and Therapeutics." Current Cancer Drug Targets 19, no. 2 (January 21, 2019): 82–100. http://dx.doi.org/10.2174/1568009618666180430130248.
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Despite advances in the treatment regimen, the high incidence rate of breast cancer (BC) deaths is mostly caused by metastasis. Recently, the aberrant epigenetic modifications, which involve DNA methylation, histone modifications and microRNA (miRNA) regulations become attractive targets to treat metastatic breast cancer (MBC). In this review, the epigenetic alterations of DNA methylation, histone modifications and miRNA regulations in regulating MBC are discussed. The preclinical and clinical trials of epigenetic drugs such as the inhibitor of DNA methyltransferase (DNMTi) and the inhibitor of histone deacetylase (HDACi), as a single or combined regimen with other epigenetic drug or standard chemotherapy drug to treat MBCs are discussed. The combined regimen of epigenetic drugs or with standard chemotherapy drugs enhance the therapeutic effect against MBC. Evidences that epigenetic changes could have implications in diagnosis, prognosis and therapeutics for MBC are also presented. Several genes have been identified as potential epigenetic biomarkers for diagnosis and prognosis, as well as therapeutic targets for MBC. Endeavors in clinical trials of epigenetic drugs against MBC should be continued although limited success has been achieved. Future discovery of epigenetic drugs from natural resources would be an attractive natural treatment regimen for MBC. Further research is warranted in translating research into clinical practice with the ultimate goal of treating MBC by epigenetic therapy in the near future.
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Venneker, Sanne, Robin van Eenige, Alwine B. Kruisselbrink, Ieva Palubeckaitė, Alice E. Taliento, Inge H. Briaire-de Bruijn, Pancras C. W. Hogendoorn, et al. "Histone Deacetylase Inhibitors as a Therapeutic Strategy to Eliminate Neoplastic “Stromal” Cells from Giant Cell Tumors of Bone." Cancers 14, no. 19 (September 27, 2022): 4708. http://dx.doi.org/10.3390/cancers14194708.
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The neoplastic “stromal” cells in giant cell tumor of bone (GCTB) harbor a mutation in the H3F3A gene, which causes alterations in the epigenome. Current systemic targeted therapies, such as denosumab, do not affect the neoplastic cells, resulting in relapse upon treatment discontinuation. Therefore, this study examined whether targeting the epigenome could eliminate the neoplastic cells from GCTB. We established four novel cell lines of neoplastic “stromal” cells that expressed the H3F3A p.G34W mutation. These cell lines were used to perform an epigenetics compound screen (n = 128), which identified histone deacetylase (HDAC) inhibitors as key epigenetic regulators in the neoplastic cells. Transcriptome analysis revealed that the neoplastic cells expressed all HDAC isoforms, except for HDAC4. Therefore, five HDAC inhibitors targeting different HDAC subtypes were selected for further studies. All GCTB cell lines were very sensitive to HDAC inhibition in both 2D and 3D in vitro models, and inductions in histone acetylation, as well as apoptosis, were observed. Thus, HDAC inhibition may represent a promising therapeutic strategy to eliminate the neoplastic cells from GCTB lesions, which remains the paramount objective for GCTB patients who require life-long treatment with denosumab.
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Ediriweera, Meran Keshawa, and Somi Kim Cho. "Targeting miRNAs by histone deacetylase inhibitors (HDACi): Rationalizing epigenetics-based therapies for breast cancer." Pharmacology & Therapeutics 206 (February 2020): 107437. http://dx.doi.org/10.1016/j.pharmthera.2019.107437.
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Matthews, Bayley G., Nikola A. Bowden, and Michelle W. Wong-Brown. "Epigenetic Mechanisms and Therapeutic Targets in Chemoresistant High-Grade Serous Ovarian Cancer." Cancers 13, no. 23 (November 29, 2021): 5993. http://dx.doi.org/10.3390/cancers13235993.
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High-grade serous ovarian cancer (HGSOC) is the most common ovarian cancer subtype, and the overall survival rate has not improved in the last three decades. Currently, most patients develop recurrent disease within 3 years and succumb to the disease within 5 years. This is an important area of research, as the major obstacle to the treatment of HGSOC is the development of resistance to platinum chemotherapy. The cause of chemoresistance is still largely unknown and may be due to epigenetics modifications that are driving HGSOC metastasis and treatment resistance. The identification of epigenetic changes in chemoresistant HGSOC enables the development of epigenetic modulating drugs that may be used to improve outcomes. Several epigenetic modulating drugs have displayed promise as drug targets for HGSOC, such as demethylating agents azacitidine and decitabine. Others, such as histone deacetylase inhibitors and miRNA-targeting therapies, demonstrated promising preclinical results but resulted in off-target side effects in clinical trials. This article reviews the epigenetic modifications identified in chemoresistant HGSOC and clinical trials utilizing epigenetic therapies in HGSOC.
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Psilopatis, Iason, Alexandros Pergaris, Kleio Vrettou, Stamatios Theocharis, and Constantinos Troungos. "Thymic Epithelial Neoplasms: Focusing on the Epigenetic Alterations." International Journal of Molecular Sciences 23, no. 7 (April 6, 2022): 4045. http://dx.doi.org/10.3390/ijms23074045.
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Thymic Epithelial Neoplasms (TENs) represent the most common tumors of the thymus gland. Epigenetic alterations are generally involved in initiation and progression of various cancer entities. However, little is known about the role of epigenetic modifications in TENs. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms thymoma, thymic carcinoma, thymic epithelial neoplasm, epigenetics, DNA methylation, HDAC and miRNA were employed and we were able to identify forty studies focused on TENs and published between 1997 and 2021. Aberrant epigenetic alterations seem to be involved in the tumorigenesis of thymomas and thymic carcinomas, with numerous studies reporting on non-coding RNA clusters and altered gene methylation as possible biomarkers in different types of TENs. Interestingly, Histone Deacetylase Inhibitors have shown potent antitumor effects in clinical trials, thus possibly representing effective epigenetic therapeutic agents in TENs. Additional studies in larger patient cohorts are, nevertheless, needed to verify the clinical utility and safety of novel epigenetic agents in the treatment of patients with TENs.
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Duan, Zhijun, Adrian Zarebski, Diego Montoya-Durango, H. Leighton Grimes, and Marshall Horwitz. "Gfi1 Coordinates Epigenetic Repression of p21Cip/WAF1 by Recruitment of Histone Lysine Methyltransferase G9a and Histone Deacetylase 1." Molecular and Cellular Biology 25, no. 23 (December 1, 2005): 10338–51. http://dx.doi.org/10.1128/mcb.25.23.10338-10351.2005.
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ABSTRACT The growth factor independent 1 (Gfi1) transcriptional regulator oncoprotein plays a crucial role in hematopoietic, inner ear, and pulmonary neuroendocrine cell development and governs cell processes as diverse as self-renewal of hematopoietic stem cells, proliferation, apoptosis, differentiation, cell fate specification, and oncogenesis. However, the molecular basis of its transcriptional functions has remained elusive. Here we show that Gfi1 recruits the histone lysine methyltransferase G9a and the histone deacetylase 1 (HDAC1) in order to modify the chromatin of genes targeted for repression by Gfi1. G9a and HDAC1 are both in a repressive complex assembled by Gfi1. Endogenous Gfi1 colocalizes with G9a, HDAC1, and K9-dimethylated histone H3. Gfi1 associates with G9a and HDAC1 on the promoter of the cell cycle regulator p21 Cip/WAF1 , resulting in an increase in K9 dimethylation at histone H3. Silencing of Gfi1 expression in myeloid cells reverses G9a and HDAC1 recruitment to p21 Cip/WAF1 and elevates its expression. These findings highlight the role of epigenetics in the regulation of development and oncogenesis by Gfi1.
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Russo, Diego, Giuseppe Damante, Efisio Puxeddu, Cosimo Durante, and Sebastiano Filetti. "Epigenetics of thyroid cancer and novel therapeutic targets." Journal of Molecular Endocrinology 46, no. 3 (February 16, 2011): R73—R81. http://dx.doi.org/10.1530/jme-10-0150.
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An increasing body of evidence suggests that epigenetic changes (DNA methylation, remodeling and post-translational modification of chromatin) play important roles in thyroid tumorigenesis, as a result of their effects on tumor-cell differentiation and proliferation. Epigenetic silencing of various thyroid-specific genes has been detected in thyroid tumors. These changes can diminish the tumor's ability to concentrate radioiodine, which dramatically reduces treatment options. Epigenetic changes in tumor-promoting and tumor-suppressor genes also contribute to the dysregulation of thyrocyte growth and other aspects of tumorigenesis, such as apoptosis, motility and invasiveness. We provide a brief overview of the mechanisms underlying epigenetic regulation of gene expression and the current methods used to investigate it. This is followed by a review of the principal epigenetic alterations detected in thyroid cancer cells, epigenetic strategies for treating thyroid cancers and data from preclinical and clinical studies (some still underway) on the use in this setting of demethylating agents and histone deacetylase inhibitors.
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Fernandes, Célio Júnior da C., Rodrigo A. Foganholi da Silva, Patrícia F. Wood, Marcel Rodrigues Ferreira, Gerson S. de Almeida, Julia Ferreira de Moraes, Fábio J. Bezerra, and Willian F. Zambuzzi. "Titanium-Enriched Medium Promotes Environment-Induced Epigenetic Machinery Changes in Human Endothelial Cells." Journal of Functional Biomaterials 14, no. 3 (February 27, 2023): 131. http://dx.doi.org/10.3390/jfb14030131.
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It is important to understand whether endothelial cells are epigenetically affected by titanium-enriched media when angiogenesis is required during bone development and it is expected to be recapitulated during osseointegration of biomaterials. To better address this issue, titanium-enriched medium was obtained from incubation of titanium discs for up to 24 h as recommended by ISO 10993-5:2016, and further used to expose human umbilical vein endothelial cells (HUVECs) for up to 72 h, when the samples were properly harvested to allow molecular analysis and epigenetics. In general, our data show an important repertoire of epigenetic players in endothelial cells responding to titanium, reinforcing protein related to the metabolism of acetyl and methyl groups, as follows: Histone deacetylases (HDACs) and NAD-dependent deacetylase sirtuin-1 (Sirt1), DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) methylcytosine dioxygenases, which in conjunction culminate in driving chromatin condensation and the methylation profile of DNA strands, respectively. Taking our data into consideration, HDAC6 emerges as important player of this environment-induced epigenetic mechanism in endothelial cells, while Sirt1 is required in response to stimulation of reactive oxygen species (ROS) production, as its modulation is relevant to vasculature surrounding implanted devices. Collectively, all these findings support the hypothesis that titanium keeps the surrounding microenvironment dynamically active and so affects the performance of endothelial cells by modulating epigenetics. Specifically, this study shows the relevance of HDAC6 as a player in this process, possibly correlated with the cytoskeleton rearrangement of those cells. Furthermore, as those enzymes are druggable, it opens new perspectives to consider the use of small molecules to modulate their activities as a biotechnological tool in order to improve angiogenesis and accelerate bone growth with benefits of a fast recovery time for patients.
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Harder, Lena, Georg Eschenburg, Antonia Zech, Neele Kriebitzsch, Benjamin Otto, Thomas Streichert, Anna-Sophie Behlich, et al. "Aberrant ZNF423 impedes B cell differentiation and is linked to adverse outcome of ETV6-RUNX1 negative B precursor acute lymphoblastic leukemia." Journal of Experimental Medicine 210, no. 11 (September 30, 2013): 2289–304. http://dx.doi.org/10.1084/jem.20130497.
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Differentiation arrest is a hallmark of acute leukemia. Genomic alterations in B cell differentiation factors such as PAX5, IKZF1, and EBF-1 have been identified in more than half of all cases of childhood B precursor acute lymphoblastic leukemia (ALL). Here, we describe a perturbed epigenetic and transcriptional regulation of ZNF423 in ALL as a novel mechanism interfering with B cell differentiation. Hypomethylation of ZNF423 regulatory sequences and BMP2 signaling result in transactivation of ZNF423α and a novel ZNF423β-isoform encoding a nucleosome remodeling and histone deacetylase complex–interacting domain. Aberrant ZNF423 inhibits the transactivation of EBF-1 target genes and leads to B cell maturation arrest in vivo. Importantly, ZNF423 expression is associated with poor outcome of ETV6-RUNX1–negative B precursor ALL patients. Our work demonstrates that ALL is more than a genetic disease and that epigenetics may uncover novel mechanisms of disease with prognostic implications.
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Kaur, Jasmine, Abdelkader Daoud, and Scott T. Eblen. "Targeting Chromatin Remodeling for Cancer Therapy." Current Molecular Pharmacology 12, no. 3 (July 29, 2019): 215–29. http://dx.doi.org/10.2174/1874467212666190215112915.
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Background: Epigenetic alterations comprise key regulatory events that dynamically alter gene expression and their deregulation is commonly linked to the pathogenesis of various diseases, including cancer. Unlike DNA mutations, epigenetic alterations involve modifications to proteins and nucleic acids that regulate chromatin structure without affecting the underlying DNA sequence, altering the accessibility of the transcriptional machinery to the DNA, thus modulating gene expression. In cancer cells, this often involves the silencing of tumor suppressor genes or the increased expression of genes involved in oncogenesis. Advances in laboratory medicine have made it possible to map critical epigenetic events, including histone modifications and DNA methylation, on a genome-wide scale. Like the identification of genetic mutations, mapping of changes to the epigenetic landscape has increased our understanding of cancer progression. However, in contrast to irreversible genetic mutations, epigenetic modifications are flexible and dynamic, thereby making them promising therapeutic targets. Ongoing studies are evaluating the use of epigenetic drugs in chemotherapy sensitization and immune system modulation. With the preclinical success of drugs that modify epigenetics, along with the FDA approval of epigenetic drugs including the DNA methyltransferase 1 (DNMT1) inhibitor 5-azacitidine and the histone deacetylase (HDAC) inhibitor vorinostat, there has been a rise in the number of drugs that target epigenetic modulators over recent years. Conclusion: We provide an overview of epigenetic modulations, particularly those involved in cancer, and discuss the recent advances in drug development that target these chromatin-modifying events, primarily focusing on novel strategies to regulate the epigenome.
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Ozair, Ahmad, Vivek Bhat, Reid S. Alisch, Atulya A. Khosla, Rupesh R. Kotecha, Yazmin Odia, Michael W. McDermott, and Manmeet S. Ahluwalia. "DNA Methylation and Histone Modification in Low-Grade Gliomas: Current Understanding and Potential Clinical Targets." Cancers 15, no. 4 (February 20, 2023): 1342. http://dx.doi.org/10.3390/cancers15041342.
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Gliomas, the most common type of malignant primary brain tumor, were conventionally classified through WHO Grades I–IV (now 1–4), with low-grade gliomas being entities belonging to Grades 1 or 2. While the focus of the WHO Classification for Central Nervous System (CNS) tumors had historically been on histopathological attributes, the recently released fifth edition of the classification (WHO CNS5) characterizes brain tumors, including gliomas, using an integration of histological and molecular features, including their epigenetic changes such as histone methylation, DNA methylation, and histone acetylation, which are increasingly being used for the classification of low-grade gliomas. This review describes the current understanding of the role of DNA methylation, demethylation, and histone modification in pathogenesis, clinical behavior, and outcomes of brain tumors, in particular of low-grade gliomas. The review also highlights potential diagnostic and/or therapeutic targets in associated cellular biomolecules, structures, and processes. Targeting of MGMT promoter methylation, TET-hTDG-BER pathway, association of G-CIMP with key gene mutations, PARP inhibition, IDH and 2-HG-associated processes, TERT mutation and ARL9-associated pathways, DNA Methyltransferase (DNMT) inhibition, Histone Deacetylase (HDAC) inhibition, BET inhibition, CpG site DNA methylation signatures, along with others, present exciting avenues for translational research. This review also summarizes the current clinical trial landscape associated with the therapeutic utility of epigenetics in low-grade gliomas. Much of the evidence currently remains restricted to preclinical studies, warranting further investigation to demonstrate true clinical utility.
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Io, Kumiko, Tomoya Nishino, Yoko Obata, Mineaki Kitamura, Takehiko Koji, and Shigeru Kohno. "Saha Suppresses Peritoneal Fibrosis in Mice." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 35, no. 3 (May 2015): 246–58. http://dx.doi.org/10.3747/pdi.2013.00089.
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ObjectiveLong-term peritoneal dialysis causes peritoneal fibrosis in submesothelial areas. However, the mechanism of peritoneal fibrosis is unclear. Epigenetics is the mechanism to induce heritable changes without any changes in DNA sequences. Among epigenetic modifications, histone acetylation leads to the transcriptional activation of genes. Recent studies indicate that histone acetylation is involved in the progression of fibrosis. Therefore, we examined the effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on the progression of peritoneal fibrosis in mice.MethodsPeritoneal fibrosis was induced by the injection of chlorhexidine gluconate (CG) into the peritoneal cavity of mice every other day for 3 weeks. SAHA, or a dimethylsulfoxide and saline vehicle, was administered subcutaneously every day from the start of the CG injections for 3 weeks. Morphologic peritoneal changes were assessed by Masson's trichrome staining, and fibrosis-associated factors were assessed by immunohistochemistry.ResultsIn CG-injected mice, a marked thickening of the submesothelial compact zone was observed. In contrast, the administration of SAHA suppressed the progression of submesothelial thickening and type III collagen accumulation in CG-injected mice. The numbers of fibroblast-specific protein-1-positive cells and α–smooth muscle actin α–positive cells were significantly decreased in the CG + SAHA group compared to that of the CG group. The level of histone acetylation was reduced in the peritoneum of the CG group, whereas it was increased in the CG + SAHA group.ConclusionsOur results indicate that SAHA can suppress peritoneal thickening and fibrosis in mice through up-regulation of histone acetylation. These results suggest that SAHA may have therapeutic potential for treating peritoneal fibrosis.
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Donia, Thoria, Sherien Khedr, Elsayed I. Salim, and Mohamed Hessien. "Trichostatin A sensitizes hepatoma cells to Taxol more than 5-Aza-dC and dexamethasone." Drug Metabolism and Personalized Therapy 36, no. 4 (April 5, 2021): 299–309. http://dx.doi.org/10.1515/dmpt-2020-0186.
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Abstract Objectives This work was designed to compare the sensitizing effects of epigenetic modifiers on cancer cells vs. that of glucocorticoids. Also, to evaluate their effects on genes involved in epigenetic changes and drug metabolism. Methods Hepatoma cells (HepG2) were treated with the anticancer drug (Taxol), with a histone deacetylase inhibitor (Trichostatin A [TSA]), DNA methyltransferase inhibitor (5-Aza-dC) or dexamethasone (DEX). Cytotoxicity was assessed by MTT assay and the apoptosis was determined by Annexin V-FITC. The expression levels of HDAC1, HDAC3, Dnmt1, Dnmt3α, CYP1A2, CYP3A4, CYP2B6, CYP2C19 and CYP2D6 were monitored by qRT-PCR. Results TSA, synergistically enhanced cells sensitivity with the anticancer effect of Taxol more than 5-Aza-dC and DEX. This was evidenced by the relative decrease in IC50 in cells cotreated with Taxol + TSA, Taxol + 5-Aza-dC or Taxol + DEX. Apoptosis was induced in 51.2, 16.9 and 41.3% of cells, respectively. In presence of Taxol, TSA induced four-fold increase in the expression of HDAC1 and downregulated Dnmt1&3α genes. CYP2D6 demonstrated progressive expression (up to 28-fold) with the increasing number of drugs. Moreover, the isoform overexpressed in cells treated with TSA + Taxol > DEX + Taxol > 5-Aza-dC + Taxol (6.4, 4.6 and 2.99, respectively). The investigated genes were clustered in two distinct subsets, where no coregulation was observed between HDAC1 and HDAC3. However, tight pairwise correlation-based cluster was seen between (CYP3A4/Dnmt3α and CYP2D6/CYP2C19). Conclusions The data reflects the sensitizing effect of acetylation modification by TSA on the responsiveness of hepatoma cells to anticancer therapy. The effect of histone deacetylase inhibition was more than hypomethylation and glucocorticoid effects. TSA exerts its role through its modulatory role on epigenetics and drugs metabolizing genes. Other modifiers (5-Aza-dC and DEX), however may adopt different mechanisms.
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Montoya-Durango, Diego E., and Kenneth S. Ramos. "Retinoblastoma family of proteins and chromatin epigenetics: a repetitive story in a few LINEs." BioMolecular Concepts 2, no. 4 (August 1, 2011): 233–45. http://dx.doi.org/10.1515/bmc.2011.027.
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AbstractThe retinoblastoma (RB) protein family in mammals is composed of three members: pRB (or RB1), p107, and p130. Although these proteins do not directly bind DNA, they associate with the E2F family of transcription factors which function as DNA sequence-specific transcription factors. RB proteins alter gene transcription via direct interference with E2F functions, as well as recruitment of transcriptional repressors and corepressors that silence gene expression through DNA and histone modifications. E2F/RB complexes shape the chromatin landscape through recruitment to CpG-rich regions in the genome, thus making E2F/RB complexes function as local and global regulators of gene expression and chromatin dynamics. Recruitment of E2F/pRB to the long interspersed nuclear element (LINE1) promoter enhances the role that RB proteins play in genome-wide regulation of heterochromatin. LINE1 elements are dispersed throughout the genome and therefore recruitment of RB to the LINE1 promoter suggests that LINE1 could serve as the scaffold on which RB builds up heterochromatic regions that silence and shape large stretches of chromatin. We suggest that mutations in RB function might lead to global rearrangement of heterochromatic domains with concomitant retrotransposon reactivation and increased genomic instability. These novel roles for RB proteins open the epigenetic-based way for new pharmacological treatments of RB-associated diseases, namely inhibitors of histone and DNA methylation, as well as histone deacetylase inhibitors.
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Abid, Farah, Muhammad Saleem, Saleha Yasir, Shumila Arshad, Sundus Qureshi, Mayyda Asif Bajwa, Sana Ashiq, Samreen Tanveer, Mehiwh Qayyum, and Kanwal Ashiq. "CANCER EPIGENETICS AND THE ROLE OF DIETARY ELEMENTS." Gomal Journal of Medical Sciences 17, no. 3 (July 16, 2020): 96–104. http://dx.doi.org/10.46903/gjms/17.03.2070.
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Cancer has been a fatal disease since many decades. Over the time, it is presented in multiple ways and is a matter of consideration as accounts for the high rate of mortality. The aim of the current review was to focus on the genetics, epigenetics factors and role of medicinal plants for the cure of this inimical disease. Related articles available in English language (2002-2018) were reviewed with help of different database, including PubMed, Springer Link, Medline, Google Scholar and ScienceDirect. In order to ensure credibility and accuracy of data only those articles were considered which are published in indexed journals i.e. Web of Science and Scopus. This project was conducted at the Department of Pharmacy, Government College University, Faisalabad, Pakistan from 02-01-2019 to 28-02-2019. The genetic machinery is vibrantly involved in the interpretation of the signals and is observed to be affected by various dietary factors. A sequence of modified activities is observed with use of these dietary elements. However, the modification is reviewed through the histone acetyltransferase (HAT), histone deacetylase (HDAC) and DNA methyl transferase (DNMTs), effecting the expression of gene. These modified genes, in turn then express the signals in multiple reformed ways. Different dietary elements that are used such as polyphenol, alkaloid and flavonoids are effective against cancer. The progression of disease involves genetics and epigenetics due to amplification, translocation and mutation during gene expression. Though, many studies have been conducted elaborating the role of plants and their ingredients which play a part in inhibition of cancerous cells by blockade of cell cycle and apoptosis; more in-depth investigations are still required to identify the new drug target and novel therapeutic modalities.
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Elangovan, Venkateswaran Ramamoorthi, Sara M. Camp, Gabriel T. Kelly, Ankit A. Desai, Djanybek Adyshev, Xiaoguang Sun, Stephen M. Black, Ting Wang, and Joe G. N. Garcia. "Endotoxin- and Mechanical Stress–Induced Epigenetic Changes in the Regulation of the Nicotinamide Phosphoribosyltransferase Promoter." Pulmonary Circulation 6, no. 4 (December 2016): 539–44. http://dx.doi.org/10.1086/688761.
Full textAbstract:
Mechanical ventilation, a lifesaving intervention for patients with acute respiratory distress syndrome (ARDS), also unfortunately contributes to excessive mechanical stress and impaired lung physiological and structural integrity. We have elsewhere established the pivotal role of increased nicotinamide phosphoribosyltransferase (NAMPT) transcription and secretion as well as its direct binding to the toll-like receptor 4 (TLR4) in the progression of this devastating syndrome; however, regulation of this critical gene in ventilator-induced lung injury (VILI) is not well characterized. On the basis of an emerging role for epigenetics in enrichment of VILI and CpG sites within the NAMPT promoter and 5′UTR, we hypothesized that NAMPT expression and downstream transcriptional events are influenced by epigenetic mechanisms. Concomitantly, excessive mechanical stress of human pulmonary artery endothelial cells or lipopolysaccharide (LPS) treatment led to both reduced DNA methylation levels in the NAMPT promoter and increased gene transcription. Histone deacetylase inhibition by trichostatin A or Sirt-1–silencing RNA attenuates LPS-induced NAMPT expression. Furthermore, recombinant NAMPT administration induced TLR4-dependent global H3K9 hypoacetylation. These studies suggest a complex epigenetic regulatory network of NAMPT in VILI and ARDS and open novel strategies for combating VILI and ARDS.
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Faldoni, Flavia Lima Costa, Cláudia Aparecida Rainho, and Silvia Regina Rogatto. "Epigenetics in Inflammatory Breast Cancer: Biological Features and Therapeutic Perspectives." Cells 9, no. 5 (May 8, 2020): 1164. http://dx.doi.org/10.3390/cells9051164.
Full textAbstract:
Evidence has emerged implicating epigenetic alterations in inflammatory breast cancer (IBC) origin and progression. IBC is a rare and rapidly progressing disease, considered the most aggressive type of breast cancer (BC). At clinical presentation, IBC is characterized by diffuse erythema, skin ridging, dermal lymphatic invasion, and peau d’orange aspect. The widespread distribution of the tumor as emboli throughout the breast and intra- and intertumor heterogeneity is associated with its poor prognosis. In this review, we highlighted studies documenting the essential roles of epigenetic mechanisms in remodeling chromatin and modulating gene expression during mammary gland differentiation and the development of IBC. Compiling evidence has emerged implicating epigenetic changes as a common denominator linking the main risk factors (socioeconomic status, environmental exposure to endocrine disruptors, racial disparities, and obesity) with IBC development. DNA methylation changes and their impact on the diagnosis, prognosis, and treatment of IBC are also described. Recent studies are focusing on the use of histone deacetylase inhibitors as promising epigenetic drugs for treating IBC. All efforts must be undertaken to unravel the epigenetic marks that drive this disease and how this knowledge could impact strategies to reduce the risk of IBC development and progression.
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Hervás-Corpión, Irati, Jorge Navarro-Calvo, Paula Martín-Climent, Marianela Iriarte-Gahete, Noelia Geribaldi-Doldán, Carmen Castro, and Luis M. Valor. "Defining a Correlative Transcriptional Signature Associated with Bulk Histone H3 Acetylation Levels in Adult Glioblastomas." Cells 12, no. 3 (January 19, 2023): 374. http://dx.doi.org/10.3390/cells12030374.
Full textAbstract:
Glioblastoma (GB) is the most prevalent primary brain cancer and the most aggressive form of glioma because of its poor prognosis and high recurrence. To confirm the importance of epigenetics in glioma, we explored The Cancer Gene Atlas (TCGA) database and we found that several histone/DNA modifications and chromatin remodeling factors were affected at transcriptional and genetic levels in GB compared to lower-grade gliomas. We associated these alterations in our own cohort of study with a significant reduction in the bulk levels of acetylated lysines 9 and 14 of histone H3 in high-grade compared to low-grade tumors. Within GB, we performed an RNA-seq analysis between samples exhibiting the lowest and highest levels of acetylated H3 in the cohort; these results are in general concordance with the transcriptional changes obtained after histone deacetylase (HDAC) inhibition of GB-derived cultures that affected relevant genes in glioma biology and treatment (e.g., A2ML1, CD83, SLC17A7, TNFSF18). Overall, we identified a transcriptional signature linked to histone acetylation that was potentially associated with good prognosis, i.e., high overall survival and low rate of somatic mutations in epigenetically related genes in GB. Our study identifies lysine acetylation as a key defective histone modification in adult high-grade glioma, and offers novel insights regarding the use of HDAC inhibitors in therapy.
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Xu, Siyuan, Siqing Wang, Shenghui Xing, Dingdang Yu, Bowen Rong, Hai Gao, Mengyao Sheng, et al. "KDM5A suppresses PML-RARα target gene expression and APL differentiation through repressing H3K4me2." Blood Advances 5, no. 17 (August 27, 2021): 3241–53. http://dx.doi.org/10.1182/bloodadvances.2020002819.
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Abstract Epigenetic abnormalities are frequently involved in the initiation and progression of cancers, including acute myeloid leukemia (AML). A subtype of AML, acute promyelocytic leukemia (APL), is mainly driven by a specific oncogenic fusion event of promyelocytic leukemia–RA receptor fusion oncoprotein (PML-RARα). PML-RARα was reported as a transcription repressor through the interaction with nuclear receptor corepressor and histone deacetylase complexes leading to the mis-suppression of its target genes and differentiation blockage. Although previous studies were mainly focused on the connection of histone acetylation, it is still largely unknown whether alternative epigenetics mechanisms are involved in APL progression. KDM5A is a demethylase of histone H3 lysine 4 di- and tri-methylations (H3K4me2/3) and a transcription corepressor. Here, we found that the loss of KDM5A led to APL NB4 cell differentiation and retarded growth. Mechanistically, through epigenomics and transcriptomics analyses, KDM5A binding was detected in 1889 genes, with the majority of the binding events at promoter regions. KDM5A suppressed the expression of 621 genes, including 42 PML-RARα target genes, primarily by controlling the H3K4me2 in the promoters and 5′ end intragenic regions. In addition, a recently reported pan-KDM5 inhibitor, CPI-455, on its own could phenocopy the differentiation effects as KDM5A loss in NB4 cells. CPI-455 treatment or KDM5A knockout could greatly sensitize NB4 cells to all-trans retinoic acid–induced differentiation. Our findings indicate that KDM5A contributed to the differentiation blockage in the APL cell line NB4, and inhibition of KDM5A could greatly potentiate NB4 differentiation.
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Venneker, Sanne, Alwine B. Kruisselbrink, Zuzanna Baranski, Ieva Palubeckaite, Inge H. Briaire-de Bruijn, Jan Oosting, Pim J. French, Erik H. J. Danen, and Judith V. M. G. Bovée. "Beyond the Influence of IDH Mutations: Exploring Epigenetic Vulnerabilities in Chondrosarcoma." Cancers 12, no. 12 (November 30, 2020): 3589. http://dx.doi.org/10.3390/cancers12123589.
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Mutations in the isocitrate dehydrogenase (IDH1 or IDH2) genes are common in enchondromas and chondrosarcomas, and lead to elevated levels of the oncometabolite D-2-hydroxyglutarate causing widespread changes in the epigenetic landscape of these tumors. With the use of a DNA methylation array, we explored whether the methylome is altered upon progression from IDH mutant enchondroma towards high-grade chondrosarcoma. High-grade tumors show an overall increase in the number of highly methylated genes, indicating that remodeling of the methylome is associated with tumor progression. Therefore, an epigenetics compound screen was performed in five chondrosarcoma cell lines to therapeutically explore these underlying epigenetic vulnerabilities. Chondrosarcomas demonstrated high sensitivity to histone deacetylase (HDAC) inhibition in both 2D and 3D in vitro models, independent of the IDH mutation status or the chondrosarcoma subtype. siRNA knockdown and RNA expression data showed that chondrosarcomas rely on the expression of multiple HDACs, especially class I subtypes. Furthermore, class I HDAC inhibition sensitized chondrosarcoma to glutaminolysis and Bcl-2 family member inhibitors, suggesting that HDACs define the metabolic state and apoptotic threshold in chondrosarcoma. Taken together, HDAC inhibition may represent a promising targeted therapeutic strategy for chondrosarcoma patients, either as monotherapy or as part of combination treatment regimens.