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Histone Modification on Parathyroid Tumors: A Review of Epigenetics.

Parathyroid tumors are very prevalent conditions among endocrine tumors, being the second most common behind thyroid tumors. Secondary hyperplasia can occur beyond benign and malignant neoplasia in parathyroid glands. Adenomas are the leading cause of hyperparathyroidism, while carcinomas represent less than 1% of the cases. Tumor suppressor gene mutations such as MEN1 and CDC73 were demonstrated to be involved in tumor development in both familiar and sporadic types; however, the epigenetic features of the parathyroid tumors are still a little-explored subject. We present a review of epigenet

Increased histone citrullination in juvenile idiopathic arthritis.

OBJECTIVE: Posttranslational modifications (PTMs) of proteins are crucial for regulating various biological processes. However, protein alteration via PTMs, and consequently, the creation of new epitopes, can induce abnormal autoimmune responses in predisposed individuals. Immunopathogenesis of several rheumatic diseases, including the most common childhood form, juvenile idiopathic arthritis (JIA), is associated with the generation of autoantibodies against such modified proteins. Dysregulated generation of neutrophil extracellular traps (NETs) can be a source of post-translationally altered

Antitheilerial Activity of the Anticancer Histone Deacetylase Inhibitors.

The apicomplexan parasite, Theileria annulata, is the most prevalent hemoprotozoan in livestock, causing significant economic losses worldwide. It is essential to develop new and improved therapeutics, as current control measures are compromised by the development of resistance against the only available antitheilerial drug, buparvaquone (BPQ). Histone deacetylase inhibitors (HDACi) were shown to treat cancer effectively and revealed in vitro antiparasitic activity against apicomplexan parasites such as Plasmodium and Toxoplasma. In this study, we investigated the antitheilerial activity of th

Histone Deacetylase Inhibitors and Papillary Thyroid Cancer.

BACKGROUND/AIM: Papillary Thyroid Cancer (PTC) is the most common type of endocrine malignancy. Although PTC has an excellent prognosis, the recurrent or metastatic disease could affect patients' survival. Recent studies show that Histone Deacetylase Inhibitors (HDACIs) might be promising anticancer agents against PTC. The aim of this review is to evaluate the role of HDACIs as an additional modality in PTC treatment and to depict the latest trends of current research on this field. MATERIALS AND METHODS: This literature review was performed using the MEDLINE database. The search strategy inc

The roles of histone deacetylases in kidney development and disease.

Histone deacetylases (HDACs) are important epigenetic regulators that mediate deacetylation of both histone and non-histone proteins. HDACs, especially class I HDACs, are highly expressed in developing kidney and subject to developmental control. HDACs play an important role in kidney formation, especial nephron progenitor maintenance and differentiation. Several lines of evidence support the critical role of HDACs in the development and progression of various kidney diseases. HDAC inhibitors (HDACis) are very effective in the prevention and treatment of kidney diseases (including kidney cance

Treatment of autoimmune encephalomyelitis with a histone deacetylase inhibitor.

We have previously shown that treatment of female NOD mice with a potent nonselective histone deacetylase inhibitor attenuated experimental autoimmune encephalomyelitis, a model for progressive multiple sclerosis. Herein we show that immunization with the MOG35-55 peptide induced prolonged upregulation of genes encoding interleukin 17A (IL-17A), aryl hydrocarbon receptor, and histone deacetylase 11 in the spinal cord whereas the subunits of IL-27, IL-27p28 and IL-27ebi3 were significantly increased in secondary lymphoid organs after a lag period. Interestingly, the nitric oxide synthase gene w

In Vivo Crosslinking of Histone and RNA-Binding Proteins.

Protein-protein interactions are essential in various cellular processes including regulation of gene expression, formation of protein complexes, and cellular signaling transduction. In particular, several proteins in the nucleus interact to regulate transcription and RNA splicing. These protein-protein interactions are short and weak and occur through transient processes, making it difficult to identify these interactions. In addition, detection of interacting partners in vitro using cell lysates cannot provide complete information due to the loss of spatial organization and changes in protei

Histone Deacetylase Inhibitors and Anaplastic Thyroid Carcinoma.

BACKGROUND/AIM: Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, remaining generally incurable. Histone deacetylase (HDAC) seems to play a role in regulating transcription of genes involved in ATC, making HDAC inhibitors (HDACI) promising anticancer drugs for ATC. The purpose of this review was to evaluate the role of HDACIs in ATC treatment and describe the latest trends of current research on this field. MATERIALS AND METHODS: This literature review was performed using the MEDLINE database. The keywords/phrases were; thyroid cancer, anaplastic, HDAC, histone

The effect of histone deacetylase inhibitors on AHSP expression.

Alpha-hemoglobin stabilizing protein (AHSP) is a molecular chaperone that can reduce the damage caused by excess free α-globin to erythroid cells in patients with impaired β-globin chain synthesis. We assessed the effect of sodium phenylbutyrate and sodium valproate, two histone deacetylase inhibitors (HDIs) that are being studied for the treatment of hemoglobinopathies, on the expression of AHSP, BCL11A (all isoforms), γ-globin genes (HBG1/2), and some related transcription factors including GATA1, NFE2, EKLF, KLF4, and STAT3. For this purpose, the K562 cell line was cultured for 2, 4, and 6

The Histone Modification Code in the Pathogenesis of Autoimmune Diseases.

Autoimmune diseases are chronic inflammatory disorders caused by a loss of self-tolerance, which is characterized by the appearance of autoantibodies and/or autoreactive lymphocytes and the impaired suppressive function of regulatory T cells. The pathogenesis of autoimmune diseases is extremely complex and remains largely unknown. Recent advances indicate that environmental factors trigger autoimmune diseases in genetically predisposed individuals. In addition, accumulating results have indicated a potential role of epigenetic mechanisms, such as histone modifications, in the development of au

Histone deacetylases and their roles in mineralized tissue regeneration.

Histone acetylation is an important epigenetic mechanism that controls expression of certain genes. It includes non-sequence-based changes of chromosomal regional structure that can alter the expression of genes. Acetylation of histones is controlled by the activity of two groups of enzymes: the histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs remove acetyl groups from the histone tail, which alters its charge and thus promotes compaction of DNA in the nucleosome. HDACs render the chromatin structure into a more compact form of heterochromatin, which makes the genes in…

Targeting histone deacetylases in T-cell lymphoma.

Histone deacetylase inhibitors (HDACi) are epigenetic modifiers with single-agent activity in patients with cutaneous and peripheral T-cell lymphoma (CTCL, PTCL). The mechanisms for this preferential activity remain unclear, and although some would term this as 'class effect,' there are differences in efficacy and safety, likely a result of the varying chemical structures/classes, histone and non-histone targets, potencies, and clinical dosing for each. Three HDACi have single-agent approval in relapsed/refractory TCL in the United States: romidepsin in CTCL and PTCL, vorinostat in CTCL, and b

Histone Deacetylases as Potential Targets for Cocaine Addiction.

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 fo

Histone deacetylases (HDACs) in frontotemporal lobar degeneration.

AIMS: Frontotemporal lobar degeneration (FTLD) is clinically and pathologically heterogeneous. Although associated with variations in MAPT, GRN and C9ORF72, the pathogenesis of these, and of other nongenetic, forms of FTLD, remains unknown. Epigenetic factors such as histone regulation by histone deacetylases (HDAC) may play a role in the dysregulation of transcriptional activity, thought to underpin the neurodegenerative process. METHODS: The distribution and intensity of HDACs 4, 5 and 6 was assessed semi-quantitatively in immunostained sections of temporal cortex with hippocampus, and cere

A combined approach for the study of histone deacetylase inhibitors.

Overexpression of histone deacetylases (HDACs), with consequent hypoacetylation of histones, is reportedly associated with transcriptional repression of tumour suppressor genes. Thus, inhibition of HDACs has emerged as a promising strategy in cancer therapy. In order to monitor the effects of potential HDAC inhibitors, a multi-level approach consisting of preliminary screening (measurement of HDAC activity and semi-quantitative evaluation of histone H4 modification profile by MALDI-TOF MS) and detailed analysis of histone modification forms (using 2-D AUT/AU PAGE and LC-ESI-IT MS) has been use…

Histone deacetylase inhibitors and rational combination therapies.

Histone deacetylase inhibitors (HDACIs) are epigenetically acting agents that modify chromatin structure and by extension, gene expression. However, they may influence the behavior and survival of transformed cells by diverse mechanisms, including promoting expression of death- or differentiation-inducing genes while downregulating the expression of prosurvival genes; acting directly to increase oxidative injury and DNA damage; acetylating and disrupting the function of multiple proteins, including DNA repair and chaperone proteins; and interfering with the function of corepressor complexes. N

Histone deacetylase complexes as caretakers of genome stability.

OBJECTIVES: In recent years, the distinct clinical presentations and elevated mortality rates of various subtypes of juvenile idiopathic arthritis (JIA) with pulmonary involvement have garnered significant attention. This study aimed to elucidate the clinical characteristics of pulmonary involvement in patients with JIA to improve clinicians' knowledge. METHODS: This single-centre retrospective study analysed the baseline data, treatment options, follow-up of sixty patients of JIA with pulmonary involvement in China. Patients with interstitial lung disease (ILD) were further classified in acc

Romidepsin: a novel histone deacetylase inhibitor for cancer.

INTRODUCTION: Romidepsin is a novel histone deacetylase (HDAC) inhibitor, with a recent approval for treatment of cutaneous T-cell lymphoma (CTCL). HDAC inhibitors represent a novel approach to anti-tumor therapy. In contrast to traditional cytotoxic chemotherapy, HDAC inhibitors target underlying epigenetic changes leading to malignant transformation. Further study of romidepsin and similar agents in solid and hematologic malignancies is ongoing. AREAS COVERED: This review discusses the development of romidepsin, its mechanism of action, pivotal clinical trials, drug toxicity and its recent

Histone deacetylase inhibitors: emerging mechanisms of resistance.

The histone deacetylase inhibitors (HDIs) have shown promise in the treatment of a number of hematologic malignancies, leading to the approval of vorinostat and romidepsin for the treatment of cutaneous T-cell lymphoma and romidepsin for the treatment of peripheral T-cell lymphoma by the U.S. Food and Drug Administration. Despite these promising results, clinical trials with the HDIs in solid tumors have not met with success. Examining mechanisms of resistance to HDIs may lead to strategies that increase their therapeutic potential in solid tumors. However, relatively few examples of drug-sele

Interpreting clinical assays for histone deacetylase inhibitors.

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 deregulat

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… post-translational lysine modifications in histones have been described: methylation, phosphorylation, SUMOylation, and ATP-ribosylation. 3 , 4 All the modifications incurred by histones form the “histone code”. … Methylation of histones 6 is controlled by histones methyltransferases (HMTs) and histones demethylases (HDMs), while histones arginine methylation is catalyzed by the protein arginine N-methyltransferases family of enzymes. 7 – 9 One, two, or three methylations are possible, with impact on gene expression …