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Research Square Apr 2024Histon deacetylase (HDAC) enzyme is one of the enzymes involved in regulating gene expression and epigenetic alternation of cells by removing acetyl groups from lysine...
Histon deacetylase (HDAC) enzyme is one of the enzymes involved in regulating gene expression and epigenetic alternation of cells by removing acetyl groups from lysine residue on a histone, allowing the histones to wrap the DNA more tightly and suppressing a tumor-suppressing gene. HDAC inhibitors play an important role in inhibiting the proliferation of tumor cells by restricting the mechanism of action of HDAC enzyme, leading to the addition of acetyl groups to lysine. Mocetinostat, also known by its chemical name (MGCD0103), is a novel isotype selective HDAC enzyme that explicitly targets HDAC isoforms inhibiting Class1(HDAC 1,2,3,8) and Class IV (HDAC11) enzymes. It was approved for treating the phase II trial of Hodgkin's lymphoma in 2010. Our study revealed that different doses of Mocetinostat inhibit the growth of glioblastoma cells, metastasis, and angiogenesis and induce the apoptosis and differentiation of glioblastoma cells C6 and T98G. Western blot has shown that MGCD0103 has many biological activities to control glioblastoma cancer cells. MGCD0103 can modulate the molecular mechanism for several pathways in cells, such as inhibition of the PI3K/AKT pathway and suppression of HDAC1 enzyme activity in charge of many biological processes in the initiation and progression of cancer. The high doses of Mocetinostat drug significantly induce apoptosis and suppress cancer cell proliferation through increased pro-apoptotic proteins (BAX) and a down level of anti-apoptotic proteins(Bid, Bcl2). Also, the mocetinostat upregulated the expression of the tumor suppressor gene and downregulated the gene expression of the E2f1 transcription factor. Additionally, MGCDO103-induced differentiation was facilitated by activating the differentiation marker GFAP and preventing the undifferentiation marker from expression (Id2, N-Myc). The MGCD0103 is a potent anticancer drug crucial in treating glioblastoma cells.
PubMed: 38645087
DOI: 10.21203/rs.3.rs-4170668/v1 -
International Journal of Molecular... May 2015Recent studies have linked histone deacetylases (HDAC) to remodeling of the heart and cardiac fibrosis in heart failure. However, the molecular mechanisms linking...
BACKGROUND
Recent studies have linked histone deacetylases (HDAC) to remodeling of the heart and cardiac fibrosis in heart failure. However, the molecular mechanisms linking chromatin remodeling events with observed anti-fibrotic effects are unknown. Here, we investigated the molecular players involved in anti-fibrotic effects of HDAC inhibition in congestive heart failure (CHF) myocardium and cardiac fibroblasts in vivo.
METHODS AND RESULTS
MI was created by coronary artery occlusion. Class I HDACs were inhibited in three-week post MI rats by intraperitoneal injection of Mocetinostat (20 mg/kg/day) for duration of three weeks. Cardiac function and heart tissue were analyzed at six week post-MI. CD90+ cardiac fibroblasts were isolated from ventricles through enzymatic digestion of heart. In vivo treatment of CHF animals with Mocetinostat reduced CHF-dependent up-regulation of HDAC1 and HDAC2 in CHF myocardium, improved cardiac function and decreased scar size and total collagen amount. Moreover, expression of pro-fibrotic markers, collagen-1, fibronectin and Connective Tissue Growth Factor (CTGF) were reduced in the left ventricle (LV) of Mocetinostat-treated CHF hearts. Cardiac fibroblasts isolated from Mocetinostat-treated CHF ventricles showed a decrease in expression of collagen I and III, fibronectin and Timp1. In addition, Mocetinostat attenuated CHF-induced elevation of IL-6 levels in CHF myocardium and cardiac fibroblasts. In parallel, levels of pSTAT3 were reduced via Mocetinostat in CHF myocardium.
CONCLUSIONS
Anti-fibrotic effects of Mocetinostat in CHF are associated with the IL-6/STAT3 signaling pathway. In addition, our study demonstrates in vivo regulation of cardiac fibroblasts via HDAC inhibition.
Topics: Animals; Benzamides; Cicatrix; Collagen; Connective Tissue Growth Factor; Disease Models, Animal; Fibroblasts; Fibronectins; Fibrosis; Gene Expression; Heart Failure; Histone Deacetylase Inhibitors; Histone Deacetylases; Interleukin-6; Myocardial Ischemia; Pyrimidines; Rats; STAT3 Transcription Factor; Signal Transduction; Ventricular Function
PubMed: 25997003
DOI: 10.3390/ijms160511482 -
Leukemia & Lymphoma Mar 2023
Topics: Humans; CREB-Binding Protein; E1A-Associated p300 Protein; Epigenesis, Genetic; Lymphoma, Non-Hodgkin; Mutation; Neoplasm Recurrence, Local
PubMed: 36642966
DOI: 10.1080/10428194.2022.2164194 -
PloS One 2016Epigenetic mechanisms have been shown to play a role in alcohol use disorders (AUDs) and may prove to be valuable therapeutic targets. However, the involvement of...
Profile of Class I Histone Deacetylases (HDAC) by Human Dendritic Cells after Alcohol Consumption and In Vitro Alcohol Treatment and Their Implication in Oxidative Stress: Role of HDAC Inhibitors Trichostatin A and Mocetinostat.
Epigenetic mechanisms have been shown to play a role in alcohol use disorders (AUDs) and may prove to be valuable therapeutic targets. However, the involvement of histone deacetylases (HDACs) on alcohol-induced oxidative stress of human primary monocyte-derived dendritic cells (MDDCs) has not been elucidated. In the current study, we took a novel approach combining ex vivo, in vitro and in silico analyses to elucidate the mechanisms of alcohol-induced oxidative stress and role of HDACs in the periphery. ex vivo and in vitro analyses of alcohol-modulation of class I HDACs and activity by MDDCs from self-reported alcohol users and non-alcohol users was performed. Additionally, MDDCs treated with alcohol were assessed using qRT-PCR, western blot, and fluorometric assay. The functional effects of alcohol-induce oxidative stress were measured in vitro using PCR array and in silico using gene expression network analysis. Our findings show, for the first time, that MDDCs from self-reported alcohol users have higher levels of class I HDACs compare to controls and alcohol treatment in vitro differentially modulates HDACs expression. Further, HDAC inhibitors (HDACi) blocked alcohol-induction of class I HDACs and modulated alcohol-induced oxidative stress related genes expressed by MDDCs. In silico analysis revealed new target genes and pathways on the mode of action of alcohol and HDACi. Findings elucidating the ability of alcohol to modulate class I HDACs may be useful for the treatment of alcohol-induced oxidative damage and may delineate new potential immune-modulatory mechanisms.
Topics: Alcohol Drinking; Antioxidants; Benzamides; Dendritic Cells; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; In Vitro Techniques; Male; Oxidative Stress; Pyrimidines; Reactive Oxygen Species
PubMed: 27249803
DOI: 10.1371/journal.pone.0156421 -
Frontiers in Molecular Biosciences 2022Enhancing the immune microenvironment in cancer by targeting the nucleic acid sensors is becoming a potent therapeutic strategy. Among the nucleic acid sensors,...
Enhancing the immune microenvironment in cancer by targeting the nucleic acid sensors is becoming a potent therapeutic strategy. Among the nucleic acid sensors, activation of the RNA sensor Retinoic Acid-inducible Gene (RIG-I) using small hairpin RNAs has been shown to elicit powerful innate and adaptive immune responses. Given the challenges inherent in pharmacokinetics and delivery of RNA based agonists, we set out to discover small molecule agonists of RIG-I using a cell-based assay. To this end, we established and validated a robust high throughput screening assay based on a commercially available HEK293 reporter cell line with a luciferase reporter downstream of tandem interferon stimulated gene 54 (ISG54) promoter elements. We first confirmed that the luminescence in this cell line is dependent on RIG-I and the interferon receptor using a hairpin RNA RIG-I agonist. We established a 96-well and a 384-well format HTS based on this cell line and performed a proof-of-concept screen using an FDA approved drug library of 1,200 compounds. Surprisingly, we found two HDAC inhibitors Entinostat, Mocetinostat and the PLK1 inhibitor Volasertib significantly enhanced ISG-luciferase activity. This luminescence was substantially diminished in the null reporter cell line indicating the increase in signaling was dependent on RIG-I expression. Combination treatment of tumor cell lines with Entinostat increased RIG-I induced cell death in a mammary carcinoma cell line that is resistant to either Entinostat or RIG-I agonist alone. Taken together, our data indicates an unexpected role for HDAC1,-3 inhibitors in enhancing RIG-I signaling and highlight potential opportunities for therapeutic combinations.
PubMed: 35237663
DOI: 10.3389/fmolb.2022.837610 -
European Review For Medical and... May 2021The article "Mocetinostat suppresses epidural fibrosis following laminectomy by inhibiting myofibroblast activation and increasing apoptosis, by W.-J. Wu, J. Wang, J....
The article "Mocetinostat suppresses epidural fibrosis following laminectomy by inhibiting myofibroblast activation and increasing apoptosis, by W.-J. Wu, J. Wang, J. Liang, Q. Zhou, Y. Liang, published in Eur Rev Med Pharmacol Sci 2020; 24 (8): 4467-4475-DOI: 10.26355/eurrev_202004_21029-PMID: 32373984" has been withdrawn from the authors due to some errors in the data. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/21029.
PubMed: 34002805
DOI: 10.26355/eurrev_202105_25801 -
Cancer Genomics & Proteomics 2017Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR) and HER2 gene. It comprises approximately 15-20% of breast... (Review)
Review
Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR) and HER2 gene. It comprises approximately 15-20% of breast cancers (BCs). Unfortunately, TNBC's treatment continues to be a clinical problem because of its relatively poor prognosis, its aggressiveness and the lack of targeted therapies, leaving chemotherapy as the mainstay of treatment. It is essential to find new therapies against TNBC, in order to surpass the resistance and the invasiveness of already existing therapies. Given the fact that epigenetic processes control both the initiation and progression of TNBC, there is an increasing interest in the mechanisms, molecules and signaling pathways that participate at the epigenetic modulation of genes expressed in carcinogenesis. The acetylation of histone proteins provokes the transcription of genes involved in cell growth, and the expression of histone deacetylases (HDACs) is frequently up-regulated in many malignancies. Unfortunately, in the field of BC, HDAC inhibitors have shown limited effect as single agents. Nevertheless, their use in combination with kinase inhibitors, autophagy inhibitors, ionizing radiation, or two HDAC inhibitors together is currently being evaluated. HDAC inhibitors such as suberoylanilidehydroxamic acid (SAHA), sodium butyrate, mocetinostat, panobinostat, entinostat, YCW1 and N-(2-hydroxyphenyl)-2-propylpentanamide have shown promising therapeutic outcomes against TNBC, especially when they are used in combination with other anticancer agents. More studies concerning HDAC inhibitors in breast carcinomas along with a more accurate understanding of the TNBC's pathobiology are required for the possible identification of new therapeutic strategies.
Topics: Antineoplastic Agents; Female; Histone Deacetylases; Humans; Molecular Targeted Therapy; Triple Negative Breast Neoplasms
PubMed: 28870998
DOI: 10.21873/cgp.20041 -
International Journal of Molecular... Jan 2022The neural crest transcription factor BRN3A is essential for the proliferation and survival of melanoma cells. It is frequently expressed in melanoma but not in normal...
The neural crest transcription factor BRN3A is essential for the proliferation and survival of melanoma cells. It is frequently expressed in melanoma but not in normal melanocytes or benign nevi. The mechanisms underlying the aberrant expression of BRN3A are unknown. Here, we investigated the epigenetic regulation of in melanocytes and melanoma cell lines treated with DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC) inhibitors. DNMT and HAT inhibition did not significantly alter BRN3A expression levels, whereas panHDAC inhibition by trichostatin A led to increased expression. Treatment with the isoform-specific HDAC inhibitor mocetinostat, but not with PCI-34051, also increased BRN3A expression levels, suggesting that class I HDACs HDAC1, HDAC2, and HDAC3, and class IV HDAC11, were involved in the regulation of BRN3A expression. Transient silencing of HDACs 1, 2, 3, and 11 by siRNAs revealed that, specifically, HDAC2 inhibition was able to increase BRN3A expression. ChIP-Seq analysis uncovered that HDAC2 inhibition specifically increased H3K27ac levels at a distal enhancer region of the gene. Altogether, our data suggest that HDAC2 is a key epigenetic regulator of BRN3A in melanocytes and melanoma cells. These results highlight the importance of epigenetic mechanisms in regulating melanoma oncogenes.
Topics: Cell Line; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Gene Silencing; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Humans; Melanocytes; Melanoma; Transcription Factor Brn-3A
PubMed: 35055045
DOI: 10.3390/ijms23020849 -
Frontiers in Cardiovascular Medicine 2023Atrial fibrosis represents a major hallmark in disease progression of atrial fibrillation (AF). We have previously shown that circulating microRNA-21 (miR-21) correlates...
BACKGROUND
Atrial fibrosis represents a major hallmark in disease progression of atrial fibrillation (AF). We have previously shown that circulating microRNA-21 (miR-21) correlates with the extent of left atrial fibrosis in patients undergoing catheter ablation for AF and can serve as a biomarker to predict ablation success. In this study, we aimed to validate the role of miR-21-5p as a biomarker in a large cohort of AF patients and to investigate its pathophysiological role in atrial remodeling.
METHODS
For the validation cohort, we included 175 patients undergoing catheter ablation for AF. Bipolar voltage maps were obtained, circulating miR-21-5p was measured, and patients were followed-up for 12 months including ECG holter monitoring. AF was simulated by tachyarrhythmic pacing of cultured cardiomyocytes, the culture medium was transferred to fibroblast, and fibrosis pathways were analysed.
RESULTS
73.3% of patients with no/minor LVAs, 51.4% of patients with moderate LVAs and only 18.2% of patients with extensive LVAs were in stable sinus rhythm (SR) 12 months after ablation ( < 0.01). Circulating miR-21-5p levels significantly correlated with the extent of LVAs and event-free survival. tachyarrhythmic pacing of HL-1 cardiomyocytes resulted in an increased miR-21-5p expression. Transfer of the culture medium to fibroblasts induced fibrosis pathways and collagen production. The HDAC1 inhibitor mocetinostat was found to inhibit atrial fibrosis development.
CONCLUSION
We validated miR-21-5p as a biomarker that reflects the extent of left atrial fibrosis in AF patients. Furthermore, we found that miR-21-5p is released from cardiomyocytes under tachyarrhythmic conditions and stimulates fibroblasts in a paracrine mode to induce collagen production.
PubMed: 36873400
DOI: 10.3389/fcvm.2023.1056134 -
Cell Death & Disease Oct 2014Acute myeloid leukemia (AML) is recognized as a complex disease of hematopoietic stem cell disorders, but its pathogenesis mechanisms, diagnosis, and treatment remain...
Acute myeloid leukemia (AML) is recognized as a complex disease of hematopoietic stem cell disorders, but its pathogenesis mechanisms, diagnosis, and treatment remain unclear. General histone deacetylase (HDAC) inhibitors have been used in blood cancers including AML, but the lack of gene specificity greatly limits their anti-cancer effects and clinical applications. Here, we found that HDAC1 expression was negatively correlated with that of Krüppel-like factor 4 (Klf4) and that AML patients with lower HDAC1 level had better prognosis. Further, knockdown of HDAC1 in leukemia cells K562, HL-60, and U937 significantly increased Klf4 expression and inhibited cell cycle progression and cell proliferation, similar results were found for HDAC inhibitors (VPA and mocetinostat). Moreover, overexpression or knockdown of Klf4 could markedly block the effects of HDAC1 overexpression or knockdown on leukemia cells in vitro and in vivo, respectively. Mechanistic analyses demonstrated that HDAC1 and Klf4 competitively bound to the promoter region of Klf4 and oppositely regulated Klf4 expression in myeloid leukemia. We identified HDAC1 as a potential specific target for repressing cell proliferation and inducing cell cycle arrest through interplay and modulation of Klf4 expression, suggests that HDAC1 and Klf4 are potential new molecular markers and targets for clinical diagnosis, prognosis, and treatment of myeloid leukemia.
Topics: Animals; Base Sequence; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; Histone Deacetylase 1; Humans; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Leukemia, Myeloid; Mice, Inbred BALB C; Mice, Nude; Molecular Sequence Data; Promoter Regions, Genetic; Sp1 Transcription Factor; Up-Regulation
PubMed: 25341045
DOI: 10.1038/cddis.2014.433