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GSE65161
Homo sapiens
24 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6. The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.
Publication Title
Mediator kinase inhibition further activates super-enhancer-associated genes in AML.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation.
Publication Title
Mediator kinase inhibition further activates super-enhancer-associated genes in AML.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation.
Publication Title
Mediator kinase inhibition further activates super-enhancer-associated genes in AML.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation.
Publication Title
Mediator kinase inhibition further activates super-enhancer-associated genes in AML.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation.
Publication Title
Mediator kinase inhibition further activates super-enhancer-associated genes in AML.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
Illumina HiSeq 2000
Description
We characterized the marine natural product cortistatin A (CA) as an inhibitor of CDK8 to determine whether pharmacologic inhibition of CDK8 regulates super-enhancer function and inhibits AML proliferation. In this series, we examine the transcriptional effect on insensitive HCT116 cells of 3hrs exposure to CA. Overall design: HCT116 cells were treated in triplicate with either DMSO or CA for 3hrs after which RNA was harvested and prepared for RNA sequencing to assess transcriptional changes.
Publication Title
Mediator kinase inhibition further activates super-enhancer-associated genes in AML.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 192 Downloadable Samples
- NextSeq 500
Description
Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T cell activation and improved function of antigen presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+Foxp3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated anti-tumor immunity and demonstrate their therapeutic potential for treatment of NSCLC. Overall design: Single-cell comparison of vehicle (control) and HDAC inhibitor (ricolinostat)-treated tumor infiltrating T cells and macrophages
Publication Title
Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Mus musculus
- 384 Downloadable Samples
- NextSeq 500
Description
Immune checkpoint blockade has shown tremendous anti-tumor potential in the clinic. However, these therapies are only effective in a subset of patients, so identification of additional immunomodulatory molecules that enhance the anti-tumor activity of these treatments may expand their clinical utility. In particular, identifying small molecules that complement existing immunotherapies has been relatively unexplored, so we performed a small molecule screen to identify compounds that can enhance co-inhibitory molecule blockade, to improve the anti-tumor adaptive immune response. Our unbiased screen identified inhibitors of cyclin-dependent kinase 4 and 6 (CDK4/6), including the FDA-approved palbociclib, as a class of small molecule compounds that exhibited significant immunostimulatory activity in vitro. In accordance with our in vitro finding of enhanced NFAT signaling, single-cell RNA-sequencing confirmed that in vivo exposure to CDK4/6 inhibitors enhanced NFAT signaling in tumor infiltrating T cells. Moreover, our results revealed that CDK4/6 inhibition up-regulated activation molecules and down-regulated suppressive molecules in these cells. CDK4/6 inhibition also increased the number of T cells with activated TCR (T cell receptor) signaling, as well as factors that are important for signal transduction downstream of TCR signaling. In summary, the impact of CDK4/6i on cell cycle progression and T cell proliferation are balanced favorably towards increased T cell recruitment and enhanced effector cell function, mediated in part by activation of the NFAT family of transcription factors. Further, our results demonstrate that CDK4/6i enhances PD-1 blockade through increased T-cell effector function and inhibition of immune suppressive cytokine production. While prolonged CDK4/6i treatment could be immunosuppressive due to adverse effects on lymphocyte proliferation, properly timed/sequenced CDK4/6i may potentiate the clinical impact of anti-PD-1/PD-L1 antibodies. As palbociclib is FDA-approved and multiple other CDK4/6 inhibitors are in clinical trials, we expect that this hypothesis will undergo rapid testing in humans. Overall design: Single-cell comparison of control and CDK4/6 inhibitor treated tumor infiltrating T cells
Publication Title
CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples