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ABSTRACT:
PROVIDER: PRJNA1165326 | ENA |
REPOSITORIES: ENA
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Project description:Plasmodium and Toxoplasma are parasites of major medical importance that belong to the Apicomplexa phylum of protozoa. These parasites transform into various stages during their life cycle and express a specific set of proteins at each stage. Although still little is known of how gene expression is controlled in Apicomplexa, histone modifications, particularly acetylation, are emerging as key regulators of parasite differentiation and stage conversion. Here, we investigated the anti-Apicomplexa effect of FR235222, a histone deacetylase (HDAC) inhibitor. We show that FR235222 is active against a variety of Apicomplexa genera, including Plasmodium and Toxoplasma, and is more potent than other HDACi such as TSA and the clinically relevant compound, pyrimethamine. We identify TgHDAC3 as the target of FR235222 in Toxoplasma tachyzoites and demonstrate the crucial role of the conserved and Apicomplexa HDAC-specific residue TgHDAC3 T99 in the inhibitory activity of the drug. We also show that FR235222 induces differentiation of the tachyzoite (replicative) into the bradyzoite (non replicative) stage. Additionally, via its anti-TgHDAC3 activity, FR235222 influences the expression of ~370 genes, a third of which are stage-specifically expressed. These results identify FR235222 as a potent HDAC inhibitor of Apicomplexa, and establish HDAC3 as a central regulator of gene expression and stage conversion in Toxoplasma and likely other Apicomplexa.
2009-03-19 | GSE15241 | GEO
Project description:ATAC sequencing data of cell lines of urological malignancies treated with epigenetic agents LAK31, Romidepsin, Quisinostat and MZ-1.
2022-09-01 | GSE191184 | GEO
Project description:We first verified that erdafitinib is synergistic with quisinostat in vitro and confirmed that the combinational treatment can significantly enhance the inhibition of tumor growth and prolong the survival in vivo for bladder cancers with FGFR3 fusions. Next, in order to understand the underlying molecular mechanisms of this synergy, we performed RNA-seq analysis. We revealed that quisinostat can concomitantly inhibit FGFR signaling with erdafitinib by suppressing the translation of FGFR3 fusions. In addition, quisinostat can also sensitize bladder cancer cells to erdafitinib by downregulating HDGF, which is a second mechanism of the synergy independent of FGFR signaling.
2022-10-11 | GSE214814 | GEO
Project description:In recent years, histone deacetylase inhibitors (HDACi) have garnered considerable interest for the treatment of adult and pediatric malignant brain tumors. However, owing to their broad-spectrum nature and inability to effectively penetrate the blood-brain barrier, HDACi have failed to provide significant clinical benefit to glioblastoma (GBM) patients to date. Moreover, global inhibition of HDACs results in widespread toxicity, highlighting the need for selective isoform targeting. While no isoform-specific HDACi are currently available, the second-generation hydroxamic acid-based HDACi quisinostat possesses sub-nanomolar specificity for class I HDAC isoforms, particularly HDAC1 and 2. Recently, we demonstrated that HDAC1 is the essential HDAC in GBM. Here, we panalyzed the neuro-pharmacokinetic, pharmacodynamic and radiation-sensitizing properties of quisinostat in preclinical models of GBM. We found that quisinostat is a well-tolerated and brain-penetrant molecule that significantly extended survival when administered in combination with radiation in vivo. The pharmacokinetic-pharmacodynamic-efficacy relationship was established by correlating free drug concentrations and evidence of target modulation in the brain with survival benefit. Together, these data provide a strong rationale for clinical development of quisinostat as a radiosensitizer for the treatment of GBM.
2023-11-23 | GSE241227 | GEO
Project description:Single end 3' RNA sequencing of embryonal carcinoma cell line 2102EP treated with epigenetic agents Quisinostat, JIB-04, Chaetocin, Mz-1, LP99, PRT4165 and GSK343. DMSO was used as solvent control. Cells were treated with the epi-drugs for 16 h.
2022-01-21 | GSE189472 | GEO
Project description:Here we performed a targeted small molecule screen on a stable, SHH-dependent murine MB cell line (SMB21). A subset of the HDAC inhibitors tested significantly inhibit tumor growth of SMB21 cells by preventing SHH pathway activation. Of note, class I HDAC inhibitors were also efficacious in suppressing growth of diverse SMO inhibitor-resistant clones of SMB21 cells. Finally, we show that the novel HDAC inhibitor Quisinostat (JNJ) targets multiple class I HDACs, is well tolerated in mouse models and robustly inhibits growth of SHH MB cells in vivo as well as in vitro. Our data provide strong evidence that Quisinostat (JNJ) or other class I HDAC inhibitors might be therapeutically useful for patients with SHH MB including those resistant to SMO inhibition.
2019-04-10 | GSE129512 | GEO
Project description:Plasmodium and Toxoplasma are parasites of major medical importance that belong to the Apicomplexa phylum of protozoa. These parasites transform into various stages during their life cycle and express a specific set of proteins at each stage. Although still little is known of how gene expression is controlled in Apicomplexa, histone modifications, particularly acetylation, are emerging as key regulators of parasite differentiation and stage conversion. Here, we investigated the anti-Apicomplexa effect of FR235222, a histone deacetylase (HDAC) inhibitor. We show that FR235222 is active against a variety of Apicomplexa genera, including Plasmodium and Toxoplasma, and is more potent than other HDACi such as TSA and the clinically relevant compound, pyrimethamine. We identify TgHDAC3 as the target of FR235222 in Toxoplasma tachyzoites and demonstrate the crucial role of the conserved and Apicomplexa HDAC-specific residue TgHDAC3 T99 in the inhibitory activity of the drug. We also show that FR235222 induces differentiation of the tachyzoite (replicative) into the bradyzoite (non replicative) stage. Additionally, via its anti-TgHDAC3 activity, FR235222 influences the expression of ~370 genes, a third of which are stage-specifically expressed. These results identify FR235222 as a potent HDAC inhibitor of Apicomplexa, and establish HDAC3 as a central regulator of gene expression and stage conversion in Toxoplasma and likely other Apicomplexa. Freshly released tachyzoites were needle-passed, and filtered using a 3-µm nucleopore membrane. Parasites were resuspended into fresh DMEM supplemented with 10% (v/v) FBS and 25 mM HEPES buffer pH7.2. Parasites were incubated in the presence of FR235222 (40 nM) or DMSO (0.1%) for 4 h at 37°C with 5% CO2. For ChIP-chip experiments freshly released tachyzoites (~5 x 109 at ~12 x 107 parasites/mL) were fixed for 15 min in 1% formaldehyde. Increase in AcH4 signals was verified by immunoblot to verify that FR235222 treatment was effective. To prepare chromatin samples, fixed parasites were lysed in MNase buffer (0.32 M Sucrose, 50 mM Tris-HCl pH7.8, 4 mM MgCl2, 3 mM CaCl2, 100 mM NaCl, 0.25% (v/v) NP40, 5% (v/v) glycerol, protease inhibitor EDTA-free cocktail (Roche)) and DNA was digested for 4 min at 37°C by MNase (2 units/mL). Digestion was stopped with 20 mM EDTA and chromatin was recovered in the soluble fraction after centrifugation at 10,000 g at 4°C; this constituted the S1 fractions. Pelleted materials were resuspended in dialysis buffer (1mM Tris-HCl pH7.8, 0.2 mM EDTA) containing 1 mM PMSF and protease inhibitor cocktail (Roche®) and dialyzed overnight at 4°C against the same solution. Then dialyzed materials were centrifuged and supernatant were harvested; this constitutes the S2 fractions. For chromatin immunoprecipitations, fractions S1 and S2 were pooled and DNA quality was verified by electrophoresis on 2% agarose gels; oligonucleosome ladder of 100-1000 bp were obtained. The histone-DNA complexes were immunoprecipitated with anti-acetyl histone H4 (Upstate®, catalog # 06-866) antibodies according to NimbleGenâs protocol (http://www.genomecenter.ucdavis.edu/expression_analysis/documents).
2010-06-21 | E-GEOD-15241 | biostudies-arrayexpress