P300-mediated adaptive conversion of glioma stem cells to vascular-like cells in response to therapeutic stress promotes tumor recurrence [ATAC_SeqIRC646]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE207807 | GEO | 2022/09/09
REPOSITORIES: GEO
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Project description:Epigenetic events, including covalent post-translational modification of histones, have frequently been demonstrated to play critical roles in tumor development and progression. The transcriptional coactivator, p300/CBP, possesses both histone acetyltransferase (HAT) activity as well as scaffolding properties that directly influence transcriptional activation of targeted genes. We have used a recently reported small molecule inhibitor of p300 HAT activity, C646, to explore the specific contribution of p300/CBP HAT activity to tumor development and progression. We find that C646 inhibits the growth of lineage-specific tumor cell lines including human melanomas through direct transcriptional regulation of cell cycle regulatory proteins. Further evaluation of the p300 HAT transcriptome in human melanoma cells using comprehensive gene expression profiling reveals that p300 HAT activity globally promotes cell cycle progression, nucleosome assembly, and the DNA damage checkpoint through direct transcriptional regulatory mechanisms. Additionally, C646 promotes sensitivity to DNA damaging agents leading to enhanced apoptosis of melanoma cells following combination treatment with cisplatin. Together our data suggest that p300 HAT activity regulates critical growth regulatory pathways in tumors and may serve as a novel therapeutic target for melanoma and other malignancies by promoting cellular responses to DNA damaging agents. Keywords: p300, small molecule inhibitor, melanoma WM35 cells grown under normal culture conditions were treated for 6 and 24 hours with compound C646 to block p300 HAT activity. A vehicle control (DMSO) was included at each time point. RNA was extracted from all 4 samples using the Qiagen RNeasy kit. RNA quality check, labeling, hybridization, initial data processing and analysis was performed by the JHMI Microarray Core Facility. Affymetrix GeneChip Human Exon 1.0 ST Array was used for this study.
2013-08-01 | E-GEOD-45981 | biostudies-arrayexpress
Project description:Epigenetic events, including covalent post-translational modification of histones, have frequently been demonstrated to play critical roles in tumor development and progression. The transcriptional coactivator, p300/CBP, possesses both histone acetyltransferase (HAT) activity as well as scaffolding properties that directly influence transcriptional activation of targeted genes. We have used a recently reported small molecule inhibitor of p300 HAT activity, C646, to explore the specific contribution of p300/CBP HAT activity to tumor development and progression. We find that C646 inhibits the growth of lineage-specific tumor cell lines including human melanomas through direct transcriptional regulation of cell cycle regulatory proteins. Further evaluation of the p300 HAT transcriptome in human melanoma cells using comprehensive gene expression profiling reveals that p300 HAT activity globally promotes cell cycle progression, nucleosome assembly, and the DNA damage checkpoint through direct transcriptional regulatory mechanisms. Additionally, C646 promotes sensitivity to DNA damaging agents leading to enhanced apoptosis of melanoma cells following combination treatment with cisplatin. Together our data suggest that p300 HAT activity regulates critical growth regulatory pathways in tumors and may serve as a novel therapeutic target for melanoma and other malignancies by promoting cellular responses to DNA damaging agents. Keywords: p300, small molecule inhibitor, melanoma
2013-08-01 | GSE45981 | GEO
Project description:The transcriptional co-activator and acetyltransferase p300 is required for fundamental cellular processes, including differentiation and growth. Here, we report that p300 forms phase separated condensates in the cell nucleus. The phase separation ability of p300 is regulated by autoacetylation and relies on its catalytic core components, including the HAT domain, the autoinhibition loop, and bromodomain. p300 condensates sequester chromatin components, such as histone H3 tail and DNA, and are amplified through binding of p300 to the nucleosome. The catalytic HAT activity of p300 is decreased due to occlusion of the active site in the phase separated droplets, a large portion of which co-localizes with chromatin regions enriched in H3K27me3. Our findings suggest a model in which p300 condensates can act as a storage pool of the protein with reduced HAT activity, allowing p300 to be compartmentalized and concentrated at poised or repressed chromatin regions.
2021-08-26 | PXD026898 | Pride
Project description:The dynamic and reversible acetylation of proteins catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) was discovered more than 2 decades ago and the enzymatic function of these enzymes are established as a major epigenetic regulatory mechanism of gene transcription. Thus, these epigenetic modifiers are involved in multiple diseases and represent attractive targets for therapeutic intervention. While HDAC inhibitors have been developed and approved by the FDA to treat certain cancers, progress on the development of drug-like HAT inhibitors has lagged. The HAT paralogs p300 and CBP (here called p300/CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes and also implicated in human pathological conditions, including cancer. Current p300/CBP HAT domain inhibitors including natural products and bisubstrate analogs such as Lys-CoA either lack potency and selectivity or suffer from poor cellular permeability. C646 is widely utilized as a tool to inhibit p300/CBP HAT activity, but its off-target activity and reactivity may limit its cellular specificity. Here, we describe A-485 as a potent, selective and drug-like p300/CBP catalytic inhibitor. We show the first high resolution (1.95Å) co-crystal structure of a pharmacologically active small molecule (A-485) bound to the catalytic active site of p300 HAT domain and demonstrate that A-485 is an acetyl-CoA competitive inhibitor of p300/CBP. A-485 selectively inhibited proliferation across lineage-specific tumor types, including several hematological malignancies and androgen receptor-positive prostate cancer. A-485 robustly inhibited the androgen receptor transcriptional program in both androgen sensitive and castrate resistant prostate cancer and inhibited tumor growth in a castration resistant xenograft model. These results demonstrate the feasibility of selectively drugging the catalytic activity of histone acetyltransferases, provide the framework for delineating the enzymatic functions of HATs, and pave the way for the development of novel therapeutics targeting HAT activity.
2017-09-27 | GSE94580 | GEO
Project description:Purpose: The goal of the study is to determine the phenotypic and functional states of glioma cells induce in response to a standard glioblastoma therapy, ionizing radiation. Methods: We performed single-cell RNA-sequencing on a patient-derived gliomasphere line isolated from a primary glioblastoma tumor. Cells were exposed to a single dose of radiation ( 8 Gy) for 2- and 7-days to elaborate their gene expression profile. Single cell suspensions and cDNA library preparation was done using 10x Genomics Chromium single cell reagent kit v3 according to manufacturer's protocol. cDNA samples were sequenced on 1 lane of NovaSeq 6000 S2 flowcell. Reads were mapped to HumanGRCh38 genome using Cell Ranger v.3.0.2. More than 600 million reads were obtained for each sample. Average number of genes detected was 5875 (SE±357). Confident read mapping rates were 81.2-87.4% with over 86.8% of reads in cells. Seurat package v3.1.1 was used for integrated analysis by Canonical correlation analysis method with 75 dimensions . PCA was used for dimensional reduction, and Cell clustering was performed using shared nearest neighbor method. Each cell cluster was annotated by a combination of the following methods 1) canonical marker expression 2) Gene Set Enrichment Analysis (GSEA) of cluster specific markers determined by Find Markers function in Seurat and 3) Co-expression modules obtained by Louvain community detection clustering method. Trajectory analysis was done with monocle 3 (version 0.2.1.3) by converting Seurat object to monocle. Results: We identified 14 distinct clusters in all samples, and found dynamic alterations in frequency and size of clusters between non-radiated and radiated cells. Louvian community detection and co-expressed gene module analysis revealed that clusters expressing mitotic and DNA repair modules were diminshed, whereas clusters expressing stemness, mesenchymal and vasculogenesis modules increased post-radiation. Conclusion: Radiation therapy induces diverse functional states in glioma cells.
2022-09-09 | GSE207725 | GEO
Project description:Purpose: The goal of the study is to determine the phenotypic and functional states of glioma cells induce in response to a standard glioblastoma therapy, ionizing radiation. Methods: We performed single-cell RNA-sequencing on non-radiated and radiated tumor cells isolated from patient-derived xenografts. Tumor-bearing mice were exposed to a single dose of radiation ( 8 Gy) and cells were isolated and FACS sorted to obtain cell suspensions for assessing gene expression. Single cell suspensions and cDNA library preparation was done using 10x Genomics Chromium single cell reagent kit v3 according to manufacturer's protocol. cDNA samples were sequenced on 1 lane of NovaSeq 6000 S2 flowcell. Reads were mapped to HumanGRCh38 genome using Cell Ranger v.3.0.2. Seurat package v3.1.1 was used for integrated analysis by Canonical correlation analysis method with 75 dimensions . PCA was used for dimensional reduction, and Cell clustering was performed using shared nearest neighbor method. Each cell cluster was annotated by a combination of the following methods 1) canonical marker expression 2) Gene Set Enrichment Analysis (GSEA) of cluster specific markers determined by Find Markers function in Seurat and 3) Co-expression modules obtained by Louvain community detection clustering method. Trajectory analysis was done with monocle 3 (version 0.2.1.3) by converting Seurat object to monocle. Results: We identified 14 clusters in non-radiated tumors and 15 clusters in radiated tumors.
2022-09-09 | GSE207726 | GEO
Project description:Purpose: The goal of the study is to determine the transcriptional changes associated with non-radiated cells, radiated cells, and sorted non-radiated, and radiation-induced endothelial and pericyte-like cells to establish the identity of the vascular-like cells
2022-09-09 | GSE207729 | GEO