Competitive inhibition of histone deacetylase activity by trichostatin A and butyrate

2007 ◽  
Vol 85 (6) ◽  
pp. 751-758 ◽  
Author(s):  
Anoushe Sekhavat ◽  
Jian-Min Sun ◽  
James R. Davie
Keyword(s):  
Histone Deacetylases ◽  
Competitive Inhibition ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Cancer Cell Line ◽  
Kinetic Studies ◽  
Competitive Inhibitor ◽  
Hdac Activity ◽  
Modeling Data ◽  
Sin3 Complex

Histone deacetylases (HDACs) play a pivotal role in gene expression through their involvement in chromatin remodeling. The abnormal targeting or retention of HDACs to DNA regulatory regions is observed in many cancers, and hence HDAC inhibitors are being tested as promising anti-tumor agents. The results of previous kinetic studies, characterizing trichostatin A (TSA), as well as butyrate, as HDAC noncompetitive inhibitors, conflict with crystallographic and homology modeling data suggesting that TSA should act as a competitive inhibitor. Our results demonstrate that each of the HDAC inhibitors TSA and butyrate inhibits HDAC activity in a competitive fashion. Co-immunoprecipitation studies show that the inhibition of HDAC1 and HDAC2 activity by TSA does not disturb the extensive level of their association in the human breast cancer cell line MCF-7. Moreover, the inhibition of HDAC activity by TSA does not interfere with the interaction of HDAC1 and HDAC2 with Sin3A, a core component of the Sin3 complex. Thus, repressor complexes such as Sin3, appear to be stable in the presence of TSA. The association of HDAC2 with transcription factor Sp1 is also not affected by TSA.

NEW AND EMERGING HDAC INHIBITORS FOR THE TREATMENT OF DISEASES

INDIAN DRUGS ◽  
2014 ◽  
Vol 51 (06) ◽  
pp. 5-15
Author(s):  
S.S Mahajan ◽  
◽  
A Chavan
Keyword(s):  
Lupus Erythematosus ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Cell Lymphoma ◽  
Human Cancer ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
New Strategy ◽  
Us Fda

Histone deacetylases (HDACs) are critical in regulating gene expression and transcription. They also play a fundamental role in regulating cellular activities such as cell proliferation, survival and differentiation. Inhibition of histone deacetylases has generated many fascinating results including a new strategy in human cancer therapy. Suberoylanilide hydroxamic acid (SAHA) and romidepsin are the two drugs approved by US FDA for the treatment of cutaneous T-cell lymphoma. The HDAC inhibitors (HDACIs) like trichostatin A and SAHA are also emerging as new promising drugs for various conditions like rheumatoid arthritis, colitis, systemic lupus erythematosus and CNS disorders. This review, along with chemical classification of HDACIs, emphasizes on the therapeutic potential of various HDACIs against different diseases.

scholarly journals Effect of Trichostatin A on Histone Deacetylases 1, 2 and 3, p21Cip1/Waf1/Sdi1, p27Kip1, and p57Kip2 Gene Expression in Breast Cancer SK-BR-3 Cell Line

2020 ◽  
Vol 5 (2) ◽  
pp. 57-62
Author(s):  
Masumeh Sanaei ◽  
Fraidoon Kavoosi
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Line ◽  
Cell Apoptosis ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Histone Deacetylation ◽  
Relative Expression Level ◽  
Hematological Cancers

Objective: DNA methylation, the covalent addition of a methyl group to cytosine, and histone modification play an important role in the establishment and maintenance of the program of gene expression. The balance of histone acetylation is determined by the activities of two groups of enzymes including histone acetyltransferases (HATs) and histone deacetylases (HDACs). Histone deacetylation is generally associated with silencing gene expression resulting in several solid tumors. HDAC inhibitors (HDACIs) are the new class of potential anticancer compounds for the treatment of the solid and hematological cancers. The current study was designed to evaluate the effect of trichostatin A (TSA) on histone deacetylases 1, 2 and 3, p21Cip1/Waf1/Sdi1 (p21), p27Kip1 (p27), and p57Kip2 (p57) gene expression in breast cancer SK-BR-3 cell line. Materials and Methods: The breast cancer SK-BR-3 line was treated with TSA. To determine cell viability, cell apoptosis, and the relative expression level of the genes, MTT assay, cell apoptosis assay, and qRT-PCR were done respectively. Results: TSA significantly inhibited cell growth, and induced apoptosis. Furthermore, this compound increased p21, p27, and p57 and decreased histone deacetylases 1, 2 and 3 gene expression significantly. Conclusion: The TSA can reactivate the p21, p27, and p57 through down-regulation of histone deacetylases 1, 2 and 3 gene expression.

scholarly journals 4-phenylbutyrate exerts stage-specific effects on cardiac differentiation via HDAC inhibition

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250267
Author(s):  
Yanming Li ◽  
Xiaofei Weng ◽  
Pingping Wang ◽  
Zezhao He ◽  
Siya Cheng ◽  
...  
Keyword(s):  
Late Stage ◽  
Histone Deacetylases ◽  
Early Stage ◽  
Trichostatin A ◽  
Es Cells ◽  
Hdac Inhibitors ◽  
Embryonic Stem ◽  
Cardiac Differentiation ◽  
Temporal Expression ◽  
Cardiac Progenitors

4-phenylbutyrate (4-PBA), a terminal aromatic substituted fatty acid, is used widely to specifically attenuate endoplasmic reticulum (ER) stress and inhibit histone deacetylases (HDACs). In this study, we investigated the effect of 4-PBA on cardiac differentiation of mouse embryonic stem (ES) cells. Herein, we found that 4-PBA regulated cardiac differentiation in a stage-specific manner just like trichostatin A (TSA), a well-known HDAC inhibitor. 4-PBA and TSA favored the early-stage differentiation, but inhibited the late-stage cardiac differentiation via acetylation. Mechanistic studies suggested that HDACs exhibited a temporal expression profiling during cardiomyogenesis. Hdac1 expression underwent a decrease at the early stage, while was upregulated at the late stage of cardiac induction. During the early stage of cardiac differentiation, acetylation favored the induction of Isl1 and Nkx2.5, two transcription factors of cardiac progenitors. During the late stage, histone acetylation induced by 4-PBA or TSA interrupted the gene silence of Oct4, a key determinant of self-renewal and pluripotency. Thereby, 4-PBA and TSA at the late stage hindered the exit from pluripotency, and attenuated the expression of cardiac-specific contractile proteins. Overexpression of HDAC1 and p300 exerted different effects at the distinct stages of cardiac induction. Collectively, our study shows that timely manipulation of HDACs exhibits distinct effects on cardiac differentiation. And the context-dependent effects of HDAC inhibitors depend on cell differentiation states marked by the temporal expression of pluripotency-associated genes.

scholarly journals A New Amidohydrolase from Bordetella or Alcaligenes Strain FB188 with Similarities to Histone Deacetylases

2004 ◽  
Vol 186 (8) ◽  
pp. 2328-2339 ◽  
Author(s):  
Christian Hildmann ◽  
Milena Ninkovic ◽  
Rüdiger Dietrich ◽  
Dennis Wegener ◽  
Daniel Riester ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Transcriptase Inhibitor ◽  
Peptide Sequencing ◽  
Inverse Pcr ◽  
Nucleotide Sequence Analysis ◽  
Significant Activity ◽  
Reading Frame ◽  
Class 1

ABSTRACT The full-length gene encoding the histone deacetylase (HDAC)-like amidohydrolase (HDAH) from Bordetella or Alcaligenes (Bordetella/Alcaligenes) strain FB188 (DSM 11172) was cloned using degenerate primer PCR combined with inverse-PCR techniques and ultimately expressed in Escherichia coli. The expressed enzyme was biochemically characterized and found to be similar to the native enzyme for all properties examined. Nucleotide sequence analysis revealed an open reading frame of 1,110 bp which encodes a polypeptide with a theoretical molecular mass of 39 kDa. Interestingly, peptide sequencing disclosed that the N-terminal methionine is lacking in the mature wild-type enzyme, presumably due to the action of methionyl aminopeptidase. Sequence database searches suggest that the new amidohydrolase belongs to the HDAC superfamily, with the closest homologs being found in the subfamily assigned acetylpolyamine amidohydrolases (APAH). The APAH subfamily comprises enzymes or putative enzymes from such diverse microorganisms as Pseudomonas aeruginosa, Archaeoglobus fulgidus, and the actinomycete Mycoplana ramosa (formerly M. bullata). The FB188 HDAH, however, is only moderately active in catalyzing the deacetylation of acetylpolyamines. In fact, FB188 HDAH exhibits significant activity in standard HDAC assays and is inhibited by known HDAC inhibitors such as trichostatin A and suberoylanilide hydroxamic acid (SAHA). Several lines of evidence indicate that the FB188 HDAH is very similar to class 1 and 2 HDACs and contains a Zn2+ ion in the active site which contributes significantly to catalytic activity. Initial biotechnological applications demonstrated the extensive substrate spectrum and broad optimum pH range to be excellent criteria for using the new HDAH from Bordetella/Alcaligenes strain FB188 as a biocatalyst in technical biotransformations, e.g., within the scope of human immunodeficiency virus reverse transcriptase inhibitor synthesis.

scholarly journals Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells

2006 ◽  
Vol 13 (4) ◽  
pp. 1237-1250 ◽  
Author(s):  
Viola Baradari ◽  
Alexander Huether ◽  
Michael Höpfner ◽  
Detlef Schuppan ◽  
Hans Scherübl
Keyword(s):  
Cell Lines ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Treatment Options ◽  
Combined Treatment ◽  
Hdac Inhibitors ◽  
Cyclin B1 ◽  
Hdac Inhibition ◽  
New Approach

Treatment options of advanced neuroendocrine tumors (NETs) are unsatisfactory. Hence, innovative therapeutic approaches are urgently needed. Inhibition of histone deacetylases (HDACs) is a promising new approach in cancer therapy. While several HDAC inhibitors have already entered clinical trials, the effect of HDAC inhibition on NET has not been investigated. Therefore, we evaluated the antineoplastic effects of three different HDAC inhibitors, trichostatin A (TSA), sodium butyrate (NaB), and MS-275, on growth and apoptosis of the gastrointestinal NET cell lines CM and BON. We could demonstrate that HDAC inhibition dose-dependently inhibited proliferation of both cell lines with IC50 values varying from the millimolar (NaB) to the micromolar (MS-275) and the nanomolar range (TSA). Moreover, HDAC inhibition potently induced apoptosis, which was accompanied by DNA-fragmentation, an up to 12-fold caspase-3 activation and downregulated Bcl-2 expression. Furthermore, HDAC inhibition resulted in cell cycle arrest at the G1–S-transition, which was associated with the suppression of cyclin D1 expression and induction of p21 and p27 expression. For BON cells, we observed an additional block in the G2/M phase, which was aligned with a downregulation of cyclin B1. In addition, combined treatment with MS-275 and somatostatin or the synthetic somatostatin analog octreotide was evaluated. Neither somatostatin nor its stable analog octreotide augmented the antiproliferative effect of MS-275 in NET cells. To conclude, our data show that HDAC inhibition is a promising new approach in the treatment of NET disease, which should be evaluated in clinical studies.

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

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

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

scholarly journals Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle

2010 ◽  
Vol 299 (2) ◽  
pp. R509-R520 ◽  
Author(s):  
Nima Alamdari ◽  
Ira J. Smith ◽  
Zaira Aversa ◽  
Per-Olof Hasselgren
Keyword(s):  
Skeletal Muscle ◽  
Histone Deacetylases ◽  
Muscle Wasting ◽  
Trichostatin A ◽  
Histone Acetyl Transferase ◽  
Hdac Activity ◽  
Protein Levels ◽  
Expression And Activity

Muscle wasting during sepsis is in part regulated by glucocorticoids. In recent studies, treatment of cultured muscle cells in vitro with dexamethasone upregulated expression and activity of p300, a histone acetyl transferase (HAT), and reduced expression and activity of the histone deacetylases-3 (HDAC3) and -6, changes that favor hyperacetylation. Here, we tested the hypothesis that sepsis and glucocorticoids regulate p300 and HDAC3 and -6 in skeletal muscle in vivo. Because sepsis-induced metabolic changes are particularly pronounced in white, fast-twitch skeletal muscle, most experiments were performed in extensor digitorum longus muscles. Sepsis in rats upregulated p300 mRNA and protein levels, stimulated HAT activity, and reduced HDAC6 expression and HDAC activity. The sepsis-induced changes in p300 and HDAC expression were prevented by the glucocorticoid receptor antagonist RU38486. Treatment of rats with dexamethasone increased expression of p300 and HAT activity, reduced expression of HDAC3 and -6, and inhibited HDAC activity. Finally, treatment with the HDAC inhibitor trichostatin A resulted in increased muscle proteolysis and expression of the ubiquitin ligase atrogin-1. Taken together, our results suggest for the first time that sepsis-induced muscle wasting may be regulated by glucocorticoid-dependent hyperacetylation caused by increased p300 and reduced HDAC expression and activity. The recent development of pharmacological HDAC activators may provide a novel avenue to prevent and treat muscle wasting in sepsis and other catabolic conditions.

Trichostatin A inducesTrypanosoma cruzihistone and tubulin acetylation: effects on cell division and microtubule cytoskeleton remodelling

Parasitology ◽  
2018 ◽  
Vol 146 (4) ◽  
pp. 543-552 ◽  
Author(s):  
Jean de Oliveira Santos ◽  
Aline Araujo Zuma ◽  
Francisca Nathalia de Luna Vitorino ◽  
Julia Pinheiro Chagas da Cunha ◽  
Wanderley de Souza ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Cell Biology ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Health Concern ◽  
Microtubule Cytoskeleton ◽  
Chromatin Compaction ◽  
Tubulin Acetylation

AbstractTrypanosoma cruzi, the causative agent of Chagas disease, is a public health concern in Latin America. Epigenetic events, such as histone acetylation, affect DNA topology, replication and gene expression. Histone deacetylases (HDACs) are involved in chromatin compaction and post-translational modifications of cytoplasmic proteins, such as tubulin. HDAC inhibitors, like trichostatin A (TSA), inhibit tumour cell proliferation and promotes ultrastructural modifications. In the present study, TSA effects on cell proliferation, viability, cell cycle and ultrastructure were evaluated, as well as on histone acetylation and tubulin expression of theT. cruziepimastigote form. Protozoa proliferation and viability were reduced after treatment with TSA. Quantitative proteomic analyses revealed an increase in histone acetylation after 72 h of TSA treatment. Surprisingly, results obtained by different microscopy methodologies indicate that TSA does not affect chromatin compaction, but alters microtubule cytoskeleton dynamics and impair kDNA segregation, generating polynucleated cells with atypical morphology. Confocal fluorescence microscopy and flow cytometry assays indicated that treated cell microtubules were more intensely acetylated. Increases in tubulin acetylation may be directly related to the higher number of parasites in the G2/M phase after TSA treatment. Taken together, these results suggest that deacetylase inhibitors represent excellent tools for understanding trypanosomatid cell biology.

scholarly journals Histone Deacetylase Inhibitor, Trichostatin A, Synergistically Enhances Paclitaxel-Induced Cytotoxicity in Urothelial Carcinoma Cells by Suppressing the ERK Pathway

2019 ◽  
Vol 20 (5) ◽  
pp. 1162 ◽  
Author(s):  
Fu-Shun Hsu ◽  
June-Tai Wu ◽  
Jing-Yi Lin ◽  
Shao-Ping Yang ◽  
Kuan-Lin Kuo ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Erk Pathway ◽  
Antitumor Effects ◽  
Nude Mouse Model ◽  
Synergistic Cytotoxicity ◽  
Histone Deacetylase Inhibitor Trichostatin

Trichostatin A (TSA), an antifungal antibiotic derived from Streptomyces, inhibits mammalian histone deacetylases, and especially, selectively inhibits class I and II histone deacetylase (HDAC) families of enzymes. TSA reportedly elicits an antiproliferative response in multifarious tumors. This study investigated the antitumor effects of TSA alone and in combination with paclitaxel when applied to two high-grade urothelial carcinoma (UC) cell lines (BFTC-905 and BFTC-909). Fluorescence-activated cell sorting, flow cytometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay were used to assess TSA’s cytotoxicity and effects on apoptosis induction. TSA induced synergistic cytotoxicity, when combined with paclitaxel (combination index < 1), resulted in concomitant suppression of paclitaxel-induced activation of phospho-extracellular signal-regulated kinase (ERK) 1/2. A xenograft nude mouse model confirmed that TSA enhances the antitumor effects of paclitaxel. These findings demonstrate that the administration of TSA in combination with paclitaxel elicits a synergistic cytotoxic response. The results of this study indicate that the chemoresistance of UC could be circumvented by combining HDAC inhibitors to target the ERK pathway.

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