Ontology highlight
ABSTRACT:
PROVIDER: PRJNA284575 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1769371.fastq.gz | Fastqsanger.gz | |||
| SRR1769372.fastq.gz | Fastqsanger.gz | |||
| SRR1769373.fastq.gz | Fastqsanger.gz | |||
| SRR1769374.fastq.gz | Fastqsanger.gz | |||
| SRR1769375.fastq.gz | Fastqsanger.gz |
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Project description:Basal-like breast cancer (BBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that BBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that basal but not luminal breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. BBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of BBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in BBC and CDK7 inhibition may be useful therapy for this challenging cancer. ChIP-Seq for H3K27ac in basal-like breast cancer and luminal-like breast cancer cell lines
2015-01-23 | E-GEOD-65201 | biostudies-arrayexpress
Project description:Basal-like breast cancer (BBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that BBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that basal but not luminal breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. BBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of BBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in BBC and CDK7 inhibition may be useful therapy for this challenging cancer.
2015-01-23 | GSE65201 | GEO
Project description:Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not ER/PR+ breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of TNBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be useful therapy for this challenging cancer. Expression microarrays in H3K27ac in triple-negative breast cancer +/- treatment with covalent CDK7 inhibitor THZ1 treatment
2015-09-24 | E-GEOD-69106 | biostudies-arrayexpress
Project description:CDK7-dependent Transcriptional Addiction in Triple-Negative Breast Cancer (Microarray)
| PRJNA284577 | ENA
Project description:Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not ER/PR+ breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of TNBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be useful therapy for this challenging cancer.
2015-09-24 | GSE69106 | GEO
Project description:CDK7-dependent Transcriptional Addition in Basal-like Breast Cancer (ChIP-Seq)
| PRJNA273393 | ENA
Project description:Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancy and accounts for the majority of thyroid cancer-related deaths. Despite intensive research, there remains no effective treatment for patients with ATC. Here, we identify THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid cancer (PTC) cells, are exceptionally sensitive to CDK7 inhibition. Analyzing both gene expression profiles and super enhancer (SE) features reveals that the SE-mediated oncogenic transcriptional amplification renders the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays discovers a number of novel cancer genes of ATC, including PPP1R15A, SMG9 and KLF2. Inhibition of PPP1R15A with Guanabenz (GBZ) or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, GBZ or THZ1 treatment sensitizes ATC cells to conventional chemotherapy. Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.
2019-03-01 | GSE120175 | GEO
Project description:Transcriptional co-acticvators inhibition is proving to be a powerful mean against cancer cells that shown a novel hallmarks named transcriptional addiction. This dependecy on co-activars activity lays on their presence in clusters of enhancer regulatory regions called Super-enhancers (SEs) that establish high level of expression of genes important for cancer phisiology such as oncogenes and master transcription factors of the cellular lineage of origin. Among these co-activators in SEs is the kinase CDK7 of the basal transcription factor TFIIH. Here, using a large panel of melanoma cell lines, we observed an overall dependency of melanoma cells in CDK7 activity by inhibiting its function through the drug THZ1. However, by chronically exposing melanoma cells to THZ1, they univocally become resistant, switching phenotype toward a mesenchymal-like state.
2020-09-18 | GSE158119 | GEO
Project description:Cyclin-dependent kinase 7 (CDK7) plays a critical role in the general regulation of RNA polymerase II-mediated transcription. However, the absence of selective CDK7 inhibitors has hindered the ability to investigate the consequences of acute and prolonged inhibition of CDK7 under normal and pathological conditions. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, CDK7-IN-1, that has the unprecedented ability to target a unique cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7 amongst the 20 known CDKs. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-cell acute lymphoblastic leukemia (T-ALL), exhibit 100-fold greater sensitivity to CDK7-IN-1 over other tumor and normal cell lines. Genome-wide expression analysis in Jurkat T-ALL indicates that CDK7-IN-1 disproportionally affects RUNX1 as well as other components of the TAL1 transcriptional network and its targets, downregulating key regulators of transcription and apoptosis critical for the T-ALL state. These oncogenes are encoded by short-lived mRNA transcripts, are associated with super-enhancers, and exhibit a strong dependency on continuous transcription for sustained expression. Therefore, pharmacological modulation of CDK7 kinase activity may define a method for the identification and treatment of tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state. Jurkat cells were treated with various drugs including a covalent inhibitor of CDK7 (CDK7-IN-1), a reversible inhibitor of CDK7 (CDK7-IN-1), Flavopiridol, Actinomycin D, and DMSO controls. Replicates are annotated.
2013-12-23 | E-GEOD-50622 | biostudies-arrayexpress
Project description:Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancy and accounts for the majority of thyroid cancer-related deaths. Despite intensive research, there remains no effective treatment for patients with ATC. Here, we identify THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid cancer (PTC) cells, are exceptionally sensitive to CDK7 inhibition. Analyzing both gene expression profiles and super enhancer (SE) features reveals that the SE-mediated oncogenic transcriptional amplification renders the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays discovers a number of novel cancer genes of ATC, including PPP1R15A, SMG9 and KLF2. Inhibition of PPP1R15A with Guanabenz (GBZ) or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, GBZ or THZ1 treatment sensitizes ATC cells to conventional chemotherapy. Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.
2019-03-01 | GSE120177 | GEO