P300/CBP
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB41478 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Targeting p300/CBP axis in lethal prostate cancer
| PRJNA682218 | ENA
Project description:C4-2B prostate cancer cells were transfected with siRNA against a non-specific (NS) sequence, siRNA specifically targeting EP300, or siRNA specifically targeting CREBBP. We tested the hypothesis that their exists different subgroups of genes that are preferentially affected by p300 or CBP depletion. Cells were treated with 10nM dihydrotestosterone (DHT) for 16 hours and total RNA was extracted to check for changes in gene expression.
2011-12-15 | E-GEOD-31873 | biostudies-arrayexpress
Project description:C4-2B prostate cancer cells were transfected with siRNA against a non-specific (NS) sequence, siRNA specifically targeting EP300, or siRNA specifically targeting CREBBP. We tested the hypothesis that their exists different subgroups of genes that are preferentially affected by p300 or CBP depletion.
2011-12-15 | GSE31873 | GEO
Project description:The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators; however, their acetylation targets, site-specific acetylation kinetics, and function in proteome regulation are incompletely understood. We combined quantitative proteomics with novel CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to show that CBP/p300 acetylates thousands of sites, including signature histone sites, as well as a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Kinetic analysis identified a subset of CBP/p300-regulated sites with very rapid (<30min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions, as well as for understanding the impact of small molecule inhibitors targeting its catalytic and bromodomain activities.
2018-06-10 | PXD005252 | Pride
Project description:Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR co-activators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, alters the transcriptome of Prostate Cancer cell models
2020-12-03 | GSE162564 | GEO
Project description:Dysregulated gene expression is one of the most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of the MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300-mediated co-activation of a distinct set of transcriptional factor complexes that are aberrantly assembled with MYB in AML cells. This therapeutic remodeling is accompanied by dynamic redistribution of CBP/P300 complexes to genes that control cellular differentiation and growth. Thus, aberrantly organized transcription factor complexes control convergent gene expression programs in AML cells. These findings establish a compelling strategy for pharmacologic reprogramming of oncogenic gene expression that supports its targeting for leukemias and other human cancers caused by dysregulated gene control.
2020-12-17 | PXD019708 | Pride
Project description:p300 and CBP are highly related histone acetyltransferase (HAT) enzymes that regulate gene expression, and their dysregulation has been linked to cancer and other diseases. p300/CBP is composed of a number of domains including a HAT domain which is inhibited by the small molecule A-485 and an acetyl-lysine binding bromodomain which was recently found to be selectively antagonized by the small molecule I-CBP112. Here we show that the combination of I-CBP112 and A-485 can synergize to inhibit prostate cancer cell proliferation. We find that the combination confers a dramatic reduction in p300 chromatin occupancy compared to the individual effects of blocking either domain alone. Accompanying this loss of p300 on chromatin, combination treatment predominantly leads to the reduction of specific mRNAs including androgen-dependent and pro-oncogenic prostate genes such as KLK3 (PSA) and c-Myc. Consistent with p300 chromatin binding directly affecting gene expression, mRNAs that are significantly reduced by combination treatment also exhibit a strong reduction in p300 chromatin occupancy at their gene promoters. The relatively few mRNAs that are up-regulated upon combination treatment show no correlation with p300 occupancy. These studies provide support for the pharmacologic advantage of concurrent targeting of two domains within one key epigenetic modification enzyme.
2019-12-31 | GSE124642 | GEO
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