Inhibition of histone deacetylation by MS-275 alleviates colitis by activating the vitamin D receptor
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ABSTRACT:
PROVIDER: PRJNA576195 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10238169_1.fastq.gz | Fastqsanger.gz | |||
| SRR10238169_2.fastq.gz | Fastqsanger.gz | |||
| SRR10238170_1.fastq.gz | Fastqsanger.gz | |||
| SRR10238170_2.fastq.gz | Fastqsanger.gz | |||
| SRR10238171_1.fastq.gz | Fastqsanger.gz |
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Project description:BACKGROUND: Ulcerative colitis (UC) is a common chronic inflammatory bowel disease without curative treatment. METHODS: We conducted gene set enrichment analysis to explore potential therapeutic agent for UC. Human colon tissue samples were collected to test H3 acetylation in UC. Both in vivo and in vitro colitis models were constructed to verify the role and mechanism of H3 acetylation modification in UC. Intestine-specific vitamin D receptor (VDR)-/- mice and VD (vitamin D)-deficient diet-fed mice were used to explore downstream molecular mechanism accordingly. RESULTS: According to the Connectivity Map database, MS-275 (class I histone deacetylase inhibitor) was the top-ranked agent, indicating potential importance of histone acetylation in the pathogenesis of UC. We then found that histone H3 acetylation was significantly decreased in the colon epithelium of UC patients and negatively associated with disease severity. MS-275 treatment inhibited histone H3 deacetylation, and subsequently attenuated nuclear factor kappa B (NF-?B)-induced inflammation, reduced cellular apoptosis, maintained epithelial barrier function, and thereby reduced colitis activity in a mouse model of colitis. We also identified VDR to be a downstream effector of MS-275. The curative effect of MS-275 on colitis was abolished in VDR-/- mice and in VD-deficient diet-fed mice and VDR directly targeted p65. In UC patients, histone H3 acetylation, VDR and zonulin-1 expression showed similar downregulation patterns and were negatively associated with disease severity. CONCLUSION: We demonstrate that MS-275 inhibits histone deacetylation and alleviates colitis by ameliorating inflammation, reducing apoptosis and maintaining intestinal epithelial barrier via VDR, providing new strategies for UC treatment.
2020-09-23 | GSE138495 | GEO
Project description:Phase I trial to study the effectiveness of combining MS-275 with isotretinoin in treating patients who have metastatic or advanced solid tumors or lymphomas. MS-275 may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Isotretinoin may help cancer cells develop into normal cells. MS-275 may increase the effectiveness of isotretinoin by making cancer cells more sensitive to the drug. MS-275 and isotretinoin may also stop the growth of solid tumors or lymphomas by stopping blood flow to the cancer. Combining MS-275 with isotretinoin may kill more cancer cells
| 2011932 | ecrin-mdr-crc
Project description:RATIONALE: MS-275 may stop the growth of cancer cells by blocking the enzymes necessary for their growth.
PURPOSE: This phase I trial is studying the side effects and best dose of MS-275 in treating patients with advanced solid tumors or lymphoma.
| 2006457 | ecrin-mdr-crc
Project description:This study describes transcriptome profiling of mouse ES cells treated with MS-275. We included RNA-Seq of ds_cDNA synthesized from double poly(A) selected mRNA RNA-Seq profiling on mouse ES cells treated with MS-275
2014-03-28 | E-GEOD-45909 | biostudies-arrayexpress
Project description:This study describes transcriptome profiling of mouse ES cells treated with MS-275. We included RNA-Seq of ds_cDNA synthesized from double poly(A) selected mRNA
2014-03-28 | GSE45909 | GEO
Project description:Because insufficiency of the Runt-related transcription factor 2 (Runx2) limits skeletal growth, there is a great deal of effort to activate Runx2 for clinical use. In this study, we found that MS-275, the class I-specific HDAC inhibitor, activates Runx2 both transcriptionally and translationally. Therefore, we performed NGS analysis to gain accurate patterns of gene expression in mouse calvaria tissue through MS-275 administration. As a result, we could get insight that treatment of MS-275 increases genes related with osteoblast differentiation and cell proliferation, and decreases genes in field of causing apoptosis.
2017-09-24 | GSE87608 | GEO
Project description:The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling on SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Further studies revealed that SALL4 suppresses these pathways indirectly by repressing CBL-B. Connectivity Map analysis revealed HDAC inhibitor MS-275 as a potential drug in treating SALL4-expressing cancers and this was confirmed using 17 lung cancer cell lines. In summary, we report for the first time that MS-275 can target the novel SALL4/CBL-B pathway in lung cancer. This lays the foundation for future clinical studies to evaluate the therapeutic efficacy of MS-275 in SALL4-positive lung cancer patients.
2015-05-16 | GSE68959 | GEO
Project description:Methods: We performed mRNA sequence analysis by deep sequencing, in triplicate, using Illumina HiSeq to assess the impact of Class1 HDAC inhibitor MS-275 in regulating gene expression in BRIN-BD11 pancreatic beta cells. The transcriptome libraries were constructed using the NEB adapters and were sequenced on at 150 nucleotide read length using the paired-end chemistry. The raw reads were subjected to Adapter and low quality reads removal by Trimmomatic -0.36v. The sequence reads that passed quality filters was mapped to the Rattus_norvegicus Rnor_6.0 using STAR , counted using feature count module of sub reads package and was normalized in DESeq2-3. Differentially expressed genes were selected based on log2-ratio change with p-value <0.05 (Student‘s t test, unpaired). Hierarchical clustering was performed with the programs Cluster (uncentered correlation; average linkage clustering) and Treeview. Results: We mapped 136,002,940 (136 million reads) reads per sample to rat genome (Rnor_6.0) and observed 97% alignment to the reference rat genome. We found that 1858 genes were up regulated and 624 genes got down regulated on MS-275 treatment (log fold change ≥±2 p value < 0.05). Inference: Gene ontology reveals that the upregulated pathways upon MS-275 treatment include endocytosis, cAMP signaling, insulin secretion, Wnt signaling PI3K-Akt signaling and thermogenesis while the downregulated genes include histone modification, chromosome organization and cell cycle regulation. The study represents first detailed mRNA profiling of BRIN-BD11 pancreatic beta cell in context of modulation of expression upon treatment with Class1 HDAC inhibitor MS-275.
2019-10-22 | GSE139147 | GEO
Project description:Toxoplasma gondii is a ubiquitous apicomplexan parasite of mammals and birds and an important pathogen of humans. IFN-g is the major mediator of host resistance against T. gondii but intriguingly, parasite-infected host cells including macrophages are severely impaired to respond to IFN-g due to defective transcriptional activation of target genes. Here, we tested the possibility that the impaired responsiveness of T. gondii-infected macrophages to IFN-g can be restored by inhibiting histone deacetylases (HDACs) using the class I-specific inhibitor MS-275. Treatment of RAW264.7 cells with MS-275 indeed increased MHC class II surface expression in infected and non-infected cells and largely abolished the inhibition of IFN-g-regulated MHC class II expression exerted by T. gondii. Genome-wide transcriptome profiling revealed that MS-275 increased mean mRNA levels of IFN-g-regulated genes particularly in non-infected macrophages. Transcript levels of 33% of IFN-g secondary response genes but only those of a few primary response genes were also increased by MS-275 in T. gondii-infected cells. Importantly, the unresponsiveness of parasite-infected cells to IFN-g was however not abolished by MS-275. Furthermore, MS-275 also up-regulated several anti-inflammatory cytokines or signaling molecules in T. gondii-infected macrophages. It additionally regulated expression of more than 2500 genes in non-infected macrophages expression of which was surprisingly counteracted by prior infection with T. gondii. FACS analysis and immunofluorescence microscopy revealed that MS-275 did not considerably diminish the number of parasite-positive cells or the intracellular replication in macrophages stimulated or not with IFN-g. Thus, a supportive therapy using MS-275 appears inappropriate for treatment of toxoplasmosis.
2017-02-10 | GSE90478 | GEO
Project description:The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling on SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Further studies revealed that SALL4 suppresses these pathways indirectly by repressing CBL-B. Connectivity Map analysis revealed HDAC inhibitor MS-275 as a potential drug in treating SALL4-expressing cancers and this was confirmed using 17 lung cancer cell lines. In summary, we report for the first time that MS-275 can target the novel SALL4/CBL-B pathway in lung cancer. This lays the foundation for future clinical studies to evaluate the therapeutic efficacy of MS-275 in SALL4-positive lung cancer patients. Cells from human lung carcinoma cell line H661 with wildtype scrambled controls or Sall4 knockdown were used for RNA extraction and hybridization on Affymetrix microarrays.
2015-05-16 | E-GEOD-68959 | biostudies-arrayexpress