HDAC complex non-enzymatic inhibitor confers therapeutic effects with minimal transcriptomic changes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA870965 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21132675_1.fastq.gz | Fastqsanger.gz | |||
| SRR21132675_2.fastq.gz | Fastqsanger.gz | |||
| SRR21132676_1.fastq.gz | Fastqsanger.gz | |||
| SRR21132676_2.fastq.gz | Fastqsanger.gz | |||
| SRR21132677_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Targeting the biological function of an HDAC complex identifies a protein interaction inhibitor that solves the longstanding specificity issue associated with enzymatic inhibition.
2022-08-21 | GSE211593 | GEO
Project description:The limited clinical utility of HDAC inhibitors for the treatment of colorectal cancer (CRC) has until now remained an unresolved conundrum. Our findings provide comprehensive mechanistic insight into the ineffectiveness that defines HDAC inhibitors as a monotherapy for CRC. We identified that inhibition of HDAC2 promotes the emergence of a super-oncogenic KRAS by inducing K5 acetylation that fosters a previously undiscovered electrostatic interaction with R67 conserved in RAF kinases. This post-translational modification facilitates an increase in the binding affinity to this family of downstream RAS effectors, which translates into an immediate and persistent hyperactivation of the downstream MAPK-signaling. The concomitant instability of its co-conspirator c-MYC enables cells selectively harboring oncogenic KRAS to enter a protective state of reversible cell cycle arrest characterized by a senescence-like phenotype. Demonstratively, preventing this phenomenon from taking place provides a compelling alternative strategy for improving the prospects of HDAC inhibitor treatment for CRC.
2019-03-31 | GSE108191 | GEO
Project description:Rationale: Myocardial fibrosis manifests progressively in several forms of cardiomyopathies. Although fibrosis depicts a reparative mechanism, maladaptation of the heart due to excessive production of extracellular matrix accelerates cardiac dysfunction. Objective: The anthraquinone Rhein, a compound from rhubarb, was examined for its anti-fibrotic potency to mitigate cardiac fibroblast-to-myofibroblast transition (FMT). Methods and Results: Primary human ventricular cardiac fibroblasts were subjected to hypoxia and characterized with proteomics, transcriptomics and cell functional techniques. Knowledge based analyses of the omics data revealed a modulation of fibrosis-associated pathways and cell cycle due to Rhein administration, whereas p53 and p21 were identified as upstream regulators involved in the manifestation of cardiac fibroblast phenotypes. Mechanistically, Rhein-mediated cellular effects were linked to the histone deacetylase (HDAC)-dependent acetylation status of p53 a posttranslational modification that acts protein stabilizing. Direct enzymatic testing revealed an inhibitory potency of Rhein for HDAC classes I/II. Functionally, Rhein inhibited collagen contraction in response to protein abundance of SMAD7, endogenous inhibitor of TGFβ1 action, thus demonstrating its anti-fibrotic property in cardiac remodeling. Conclusion: In conclusion, this study identifies Rhein as a novel potent HDAC inhibitor and provides evidence that Rhein may contribute to the treatment of cardiac fibrosis as anti-fibrotic agent. As readily available drug with approved safety, Rhein constitutes a promising potential therapeutic approach in the supplemental and protective intervention of cardiac fibrosis.
2020-04-17 | GSE136039 | GEO
Project description:Here, we examined mouse brain trancriptional changes 1 hour after the 10th daily i.p. treament with one of the four following treaments: i) vehicle control (45% saline, 45% PEG-400 and 10% DMSO administered at 7.5mL/kg), ii) Cpd-60, 45mg/kg , administered at 7.5mL/kg or iii) SAHA, 25mg/kg, administered at 5mL/kg) or iv) CI-994, 10mg/kg, administered at 5mL/kg. Cpd-60 is a benzamide HDAC inhibitor with selectivity for class I HDAC subtypes HDAC1 and HDAC2; CI-994 is a benzamide inhibitor with selectivity for HDACs1,2 and 3; SAHA is a hydroxamic acid HDAC inhibitor with selectivity for class I HDAC subtypes 1,2, and 3 and the class II HDAC subtype HDAC 6. We examined transcript differences using the Illumnia WG-6 2.0 whole genome expression array and profiled 3 specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from each of 36 mice (n=6 mice / treatment group) . For application to array chips, we pooled two biological replicates from like treatment and brain region-groups such that 36 samples were applied in total: 4 treatment groups x 3 brain regions per treament group x 3 pools of two samples each for each treatment/brain region.
2013-05-29 | GSE47452 | GEO
Project description:HDAC Inhibitor-Induced Acetylation of KRAS Confers A Pro-Oncogenic Effect Limiting Treatment Response in Colorectal Cancer
| PRJNA422779 | ENA
Project description:Here, we examined mouse brain trancriptional changes 1 hour after the 10th daily i.p. treament with one of the four following treaments: i) vehicle control (45% saline, 45% PEG-400 and 10% DMSO administered at 7.5mL/kg), ii) Cpd-60, 45mg/kg , administered at 7.5mL/kg or iii) SAHA, 25mg/kg, administered at 5mL/kg) or iv) CI-994, 10mg/kg, administered at 5mL/kg. Cpd-60 is a benzamide HDAC inhibitor with selectivity for class I HDAC subtypes HDAC1 and HDAC2; CI-994 is a benzamide inhibitor with selectivity for HDACs1,2 and 3; SAHA is a hydroxamic acid HDAC inhibitor with selectivity for class I HDAC subtypes 1,2, and 3 and the class II HDAC subtype HDAC 6. We examined transcript differences using the Illumnia WG-6 2.0 whole genome expression array and profiled 3 specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from each of 36 mice (n=6 mice / treatment group) . For application to array chips, we pooled two biological replicates from like treatment and brain region-groups such that 36 samples were applied in total: 4 treatment groups x 3 brain regions per treament group x 3 pools of two samples each for each treatment/brain region. Treatment groups: All adult male, C57BL/6 mice (n=6mice/treatment group) were sacrificed by rapid cervical dislocation and decapitation 1 hour after the tenth daily i.p. injection with one of the four following treaments: i) vehicle control (45% saline, 45% PEG-400 and 10% DMSO administered at 7.5mL/kg), ii) Cpd-60, 45mg/kg , administered at 7.5mL/kg or iii) SAHA, 25mg/kg, administered at 5mL/kg) or iv) CI-994, 10mg/kg, administered at 5mL/kg. Brains were removed, frozen immediately on dry ice and stored at -80°C until use. Frozen mouse brains (n = 6/ treatment group) were rapidly dissected at 4°C, isolating medial prefrontal cortex, nucleus accumbens and hippocampus. RNA was isolated using the Qiagen RNeasy Lipid Tissue mini kit, RNA concentration was determined using a NanoDrop spectrophotometer and quality was assessed using Agilent Bioanalyzer PICO chips, with the RNA Integrity Number (RIN) determined at 7.0-8.8 for all samples assayed, indicative of good RNA quality. For microarray experiments on Illumina MouseWG-6 BeadChips, RNA samples were pooled from two biological replicates such that the total number of samples was 36 (3 treatment groups x 3 brain regions x 3 RNA pools representing two mice per pool). All microarray analysis and gene set analysis (GSA) was performed using GeneSpring software (v.11.5.1) with raw signals adjusted using quantile normalization and baseline transformation with the median signal in all samples set to zero. Data were included in subsequent analyses if the normalized signal, thresholded at 0.8, was ‘present’ for 3 of 3 replicates for like treatment and tissue groups.
2013-05-29 | E-GEOD-47452 | biostudies-arrayexpress
Project description:Natural Killer/T-cell lymphoma (NKTL) is a rare type of aggressive and heterogeneous non-Hodgkin's lymphoma (NHL) with poor prognosis and limited therapeutic options. Here, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating relapsed/refractory NKTL patients, achieving an overall response rate of 39.3%, with 17.9% complete response rate. However, the clinical response to chidamide remains variable as more than half of the patients exhibit primary resistance, limiting its utility in NKTL treatment. To unravel the resistance mechanisms of chidamide, we performed integrative transcriptomic and chromatin profiling of sensitive and resistant NKTL cells. Our results revealed that aberrant JAK-STAT signaling remodels the chromatin and confers resistance to chidamide. Subsequently, inhibition of JAK-STAT activity could overcome resistance to chidamide by reprogramming the chromatin from a resistant to sensitive state, leading to synergistic anti-tumor effect. More importantly, our clinical data demonstrated that combinatorial therapy with chidamide and JAK inhibitor ruxolitinib is effective against chidamide-resistant NKTL. In addition, we identified TNFRSF8 (CD30), a downstream target of JAK-STAT pathway, as a potential biomarker that could predict NKTL sensitivity to chidamide. Collectively, our study suggests that chidamide, in combination with JAK-STAT inhibitors, can be a novel targeted therapy in the standard of care for NKTL.
2023-03-02 | GSE152185 | GEO
Project description:Although fibrosis depicts a reparative mechanism, maladaptation of the heart due to excessive production of extracellular matrix accelerates cardiac dysfunction. The anthraquinone Rhein was examined for its anti-fibrotic potency to mitigate cardiac fibroblast-to-myofibroblast transition (FMT). Primary human ventricular cardiac fibroblasts were subjected to hypoxia and characterized with proteomics, transcriptomics and cell functional techniques. Knowledge based analyses of the omics data revealed a modulation of fibrosis-associated pathways and cell cycle due to Rhein administration during hypoxia, whereas p53 and p21 were identified as upstream regulators involved in the manifestation of cardiac fibroblast phenotypes. Mechanistically, Rhein-mediated cellular effects were linked to the histone deacetylase (HDAC)-dependent acetylation status of p53 a posttranslational modification that acts protein stabilizing. Direct enzymatic testing revealed an inhibitory potency of Rhein for HDAC classes I/II. Functionally, Rhein inhibited collagen contraction in response to protein abundance of SMAD7, thus demonstrating its anti-fibrotic property in cardiac remodeling. In conclusion, this study identifies Rhein as a novel potent HDAC inhibitor and provides evidence that Rhein may contribute to the treatment of cardiac fibrosis as anti-fibrotic agent. As readily available drug with approved safety, repurposing of Rhein constitutes a promising potential therapeutic approach in the supplemental and protective intervention of cardiac fibrosis.
2020-03-23 | PXD016731 | Pride
Project description:Epigenetic therapies have emerged as an up-and-coming strategy avenue for treating cancer treatmentmalignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by merging pharmacophores. Among them, compound (R)-23a stood out due to balanced inhibition of DNMT1 and HDAC, along with excellent anti-tumor effects in vitro by stimulating both histone acetylation and DNA methylation. Notably, treatment with compound (R)-23a resulted in a significant anti-tumor effect (TGI = 98%) on MV-4-11 xenograft models, surpassing that achieved with combination therapy. Additionally, compound (R)-23a demonstrated the ability to dramatically reduce tumor volume or even induce tumor regression in MC38 murine colon cancer models. However, this effect was compromised under conditions of immune deficiency. In conclusion, the novel DNMT1/HDAC dual inhibitor (R)-23a holds promise for the development of multiple-target anti-AML agents and tumor immunotherapy.
2024-09-10 | GSE264565 | GEO
Project description:H929 human myeloma cells were exposed to aminopeptidase inhibitor (CHR-2797), HDAC inhibitor (CHR-3996), or a combinaion of the two agents, for 24 hours. Following this treatment RNA was extracted and microarrays used to determine gene expression changes. Myeloma cells were exposed to chemotherapeutic agent for 24 hours.
2014-01-24 | E-GEOD-20405 | biostudies-arrayexpress