CDK7 inhibition suppresses Castration-Resistant Prostate Cancer through MED1 inactivation
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ABSTRACT:
PROVIDER: PRJNA515688 | ENA |
REPOSITORIES: ENA
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Project description:We performed RNA-seq and ChIP-seq in three prostate cell lines (VCaP, LNCaP and DU145) to ascertain the role of the mediator complex MED1 in AR signaling. Upon androgen stimulation, MED1 undergoes phosphorylation by CDK7 and physically engages with AR at super-enhancer sites, which is essential for AR-mediated transcription. The CDK7 specific inhibitor THZ1 blunts AR-dependent neoplastic growth by preventing the co-recruitment of AR/MED1 in a genome-wide fashion, and reverts the enzalutamide resistance characterized by hyper-phosphorylated MED1. The effect of THZ1 phenocopies that for MED1 and CDK7 knockdown.
2019-08-20 | GSE125245 | GEO
Project description: Not available
| S-EPMC7202356 | biostudies-literature
Project description:Transcriptional profiling of primary Cdk7lox/lox MEFs comparing Adeno-Cre vs Adeno-GFP infected controls. Samples were obtained 7 days after the Adeno-Cre mediated elimination of Cdk7. Goal was to determine the effects of Cdk7 elimination on RNA polII-mediated transcription. Two-condition experiment, Adeno-Cre vs. Adeno-GFP infected Cdk7lox/lox MEFs. Biological replicates: 10 independent primary MEF preparations.
2012-04-17 | E-GEOD-36050 | biostudies-arrayexpress
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, MM1S, Loucy, and HeLa (WT and Dox-inducible CDK7 mutant) 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.
2014-06-22 | E-GEOD-50624 | biostudies-arrayexpress
Project description:Med1 overexpression leads to induction of a wide spectrum of genes. Adenovirally-driven overexpression of Med1 in mouse liver stimulates hepatocyte DNA synthesis with enhanced expression of DNA replication, cell cycle control and liver specific genes as observed at day 3 and day 5 post injection. Med1 gene is amplified in a number of cancers so in this study we tested the hypothesis that Med1 by itself has the capacity to induce cell proliferation. Analysis of the Med1- induced gene expression showed a robust induction of a wide spectrum of genes involved in hepatocellular proliferation.
2013-07-18 | GSE48950 | GEO
Project description:Med1 overexpression leads to induction of a wide spectrum of genes. Adenovirally-driven overexpression of Med1 in mouse liver stimulates hepatocyte DNA synthesis with enhanced expression of DNA replication, cell cycle control and liver specific genes as observed at day 3 and day 5 post injection. Med1 gene is amplified in a number of cancers so in this study we tested the hypothesis that Med1 by itself has the capacity to induce cell proliferation. Analysis of the Med1- induced gene expression showed a robust induction of a wide spectrum of genes involved in hepatocellular proliferation. Med1 floxed mice (Med1fl/fl) were injected with Ad-His-Med1 (adenovirus expressing Med1 gene) via tail vein and killed 3 or 5 days after injection. Ad-LacZ (adenovirus expression beta-galactosidase gene) injected mouse liver served as control. Total RNA were isolated from the liver and subjected to the microarray.
2013-07-18 | E-GEOD-48950 | biostudies-arrayexpress
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:Aberrant activation of the androgen receptor (AR) plays a key role in the progression of prostate cancer. Current strategies to ablate AR signalling are circumvented when castration resistant prostate cancer (CRPC) emerges. Cyclin dependent kinase 7 (CDK7) is necessary for transcription and regulates cell cycle progression, two processes that are commonly deregulated in CRPC. Emerging evidence also suggests a pivotal role for CDK7 in AR-driven transcription, providing a rationale for targeting it in prostate cancer. CT7001, an orally bioavailable compound, was used to achieve pharmacological inhibition of CDK7. CT7001 preferentially engaged with CDK7, resulting in suppression of proliferation, cell cycle arrest, and induction of apoptosis in prostate cancer cell lines. Additionally, CT7001 interfered with transcription mediated by full-length AR as well as constitutively active AR splice variants. Oral administration of CT7001 alone effectively repressed growth in CRPC xenografts, while co-administration with enzalutamide resulted in considerably greater growth inhibition. Transcriptome analysis of treated xenografts affirmed the additive relationship between CT7001 and enzalutamide, both of which targeted pathways involved in AR signalling and cell cycle control.
2023-04-20 | GSE198488 | GEO
Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.
2023-10-11 | MTBLS8034 | MetaboLights
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