scholarly journals Inhibition of HDAC Enzymes Contributes to Differential Expression of Pro-Inflammatory Proteins in the TLR-4 Signaling Cascade

2020 ◽  
Vol 21 (23) ◽  
pp. 8943
Author(s):  
Ulrike Weiss ◽  
Moritz Möller ◽  
Sayed Adham Husseini ◽  
Christine Manderscheid ◽  
Julia Häusler ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Inflammatory Responses ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Class I ◽  
Iκb Kinase ◽  
Independent Functions ◽  
Inflammatory Proteins ◽  
Cox 2 ◽  
Rna Stabilization

Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1–3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.

scholarly journals HDAC inhibitors impair Fshb subunit expression in murine gonadotrope cells

2019 ◽  
Vol 62 (2) ◽  
pp. 67-78 ◽  
Author(s):  
Gauthier Schang ◽  
Chirine Toufaily ◽  
Daniel J Bernard
Keyword(s):  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Class I ◽  
Subunit Expression ◽  
Beta Subunit Gene ◽  
Underlying Mechanisms

Fertility is dependent on follicle-stimulating hormone (FSH), a product of gonadotrope cells of the anterior pituitary gland. Hypothalamic gonadotropin-releasing hormone (GnRH) and intra-pituitary activins are regarded as the primary drivers of FSH synthesis and secretion. Both stimulate expression of the FSH beta subunit gene (Fshb), although the underlying mechanisms of GnRH action are poorly described relative to those of the activins. There is currently no consensus on how GnRH regulates Fshb transcription, as results vary across species and between in vivo and in vitro approaches. One of the more fully developed models suggests that the murine Fshb promoter is tonically repressed by histone deacetylases (HDACs) and that GnRH relieves this repression, at least in immortalized murine gonadotrope-like cells (LβT2 and αT3-1). In contrast, we observed that the class I/II HDAC inhibitor trichostatin A (TSA) robustly inhibited basal, activin A-, and GnRH-induced Fshb mRNA expression in LβT2 cells and in primary murine pituitary cultures. Similar results were obtained with the class I specific HDAC inhibitor, entinostat, whereas two class II-specific inhibitors, MC1568 and TMP269, had no effects on Fshb expression. Collectively, these data suggest that class I HDACs are positive, not negative, regulators of Fshb expression in vitro and that, contrary to earlier reports, GnRH may not stimulate Fshb by inhibiting HDAC-mediated repression of the gene.

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.

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.

scholarly journals Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

2018 ◽  
Vol 49 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Patrick Lugenbiel ◽  
Katharina Govorov ◽  
Ann-Kathrin Rahm ◽  
Teresa Wieder ◽  
Dominik Gramlich ◽  
...  
Keyword(s):  
Action Potential ◽  
Ion Channel ◽  
Action Potential Duration ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Class I ◽  
K Channel ◽  
Hdac Inhibition ◽  
Atrial Cardiomyocytes ◽  
Channel Expression

Background/Aims: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. Methods: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K+ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. Results: Global HDAC inhibition increased histone acetylation and prolonged APD90 in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K+ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K+ channel remodeling. Conclusion: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.

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.

Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases

2015 ◽  
Vol 75 (3) ◽  
pp. 593-600 ◽  
Author(s):  
Maartje C P Cleophas ◽  
Tania O Crişan ◽  
Heidi Lemmers ◽  
Helga Toenhake-Dijkstra ◽  
Gianluca Fossati ◽  
...  
Keyword(s):  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Hdac Inhibitors ◽  
Class I ◽  
Acute Gout ◽  
Monosodium Urate ◽  
Healthy Donors ◽  
Anti Inflammatory

ObjectivesAcute gouty arthritis is caused by endogenously formed monosodium urate (MSU) crystals, which are potent activators of the NLRP3 inflammasome. However, to induce the release of active interleukin (IL)-1β, an additional stimulus is needed. Saturated long-chain free fatty acids (FFAs) can provide such a signal and stimulate transcription of pro-IL-1β. In contrast, the short-chain fatty acid butyrate possesses anti-inflammatory effects. One of the mechanisms involved is inhibition of histone deacetylases (HDACs). Here, we explored the effects of butyrate on MSU+FFA-induced cytokine production and its inhibition of specific HDACs.MethodsFreshly isolated peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with MSU and palmitic acid (C16.0) in the presence or absence of butyrate or a synthetic HDAC inhibitor. Cytokine responses were measured with ELISA and quantitative PCR. HDAC activity was measured with fluorimetric assays.ResultsButyrate decreased C16.0+MSU-induced production of IL-1β, IL-6, IL-8 and IL-1β mRNA in PBMCs from healthy donors. Similar results were obtained in PBMCs isolated from patients with gout. Butyrate specifically inhibited class I HDACs. The HDAC inhibitor, panobinostat and the potent HDAC inhibitor, ITF-B, also decreased ex vivo C16.0+MSU-induced IL-1β production.ConclusionsIn agreement with the reported low inhibitory potency of butyrate, a high concentration was needed for cytokine suppression, whereas synthetic HDAC inhibitors showed potent anti-inflammatory effects at nanomolar concentrations. These novel HDAC inhibitors could be effective in the treatment of acute gout. Moreover, the use of specific HDAC inhibitors could even improve the efficacy and reduce any potential adverse effects.

scholarly journals Inhibition of Polyomavirus ori-Dependent DNA Replication by mSin3B

2002 ◽  
Vol 76 (23) ◽  
pp. 11809-11818 ◽  
Author(s):  
An-Yong Xie ◽  
William R. Folk
Keyword(s):  
Dna Replication ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Class Ii ◽  
T Antigen ◽  
Class I ◽  
Large T Antigen ◽  
Transcriptional Corepressor ◽  
Independent Mechanism

ABSTRACT When tethered in cis to DNA, the transcriptional corepressor mSin3B inhibits polyomavirus (Py) ori-dependent DNA replication in vivo. Histone deacetylases (HDACs) appear not to be involved, since tethering class I and class II HDACs in cis does not inhibit replication and treating the cells with trichostatin A does not specifically relieve inhibition by mSin3B. However, the mSin3B L59P mutation that impairs mSin3B interaction with N-CoR/SMRT abrogates inhibition of replication, suggesting the involvement of N-CoR/SMRT. Py large T antigen interacts with mSin3B, suggesting an HDAC-independent mechanism by which mSin3B inhibits DNA replication.

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