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Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [SLAM-seq]

ABSTRACT: Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [SLAM-seq]

PROVIDER: PRJNA659371 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12516335.fastq.gz	Fastqsanger.gz
	SRR12516336.fastq.gz	Fastqsanger.gz
	SRR12516337.fastq.gz	Fastqsanger.gz
	SRR12516338.fastq.gz	Fastqsanger.gz
	SRR12516339.fastq.gz	Fastqsanger.gz

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Similar Datasets

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [SLAM-seq]

Project description:Castration resistant prostate cancers (CRPCs) lose sensitivity to androgen deprivation therapies but frequently remain dependent on oncogenic transcription driven by androgen receptor (AR) and its splice variants. To discover novel modulators of AR variant activity, we used a lysate-based small molecule microarray (SMM) assay and identified KI-ARv-03 as an AR variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742 , an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo , oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.

2020-10-05 | GSE156884 | GEO

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ChIP-seq]

2020-10-05 | GSE156882 | GEO

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ATAC-seq]

2020-10-05 | GSE156881 | GEO

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 InhibitorsModulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

Project description:Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 InhibitorsModulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

| PRJNA659344 | ENA

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ChIP-seq]

Project description:Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ChIP-seq]

| PRJNA659348 | ENA

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ATAC-seq]

Project description:Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ATAC-seq]

| PRJNA659350 | ENA

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 InhibitorsModulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-10-05 | GSE156885 | GEO

Transcription bodies regulate gene expression by sequestering CDK9 [SLAM-seq I]

Project description:Transcription bodies regulate gene expression by sequestering CDK9 [SLAM-seq I]

| PRJNA984207 | ENA

Transcription bodies regulate gene expression by sequestering CDK9 [SLAM-seq II]

Project description:Transcription bodies regulate gene expression by sequestering CDK9 [SLAM-seq II]

| PRJNA1043072 | ENA

Transcription bodies regulate gene expression by sequestering CDK9 [SLAM-seq I]

Project description:The localization of transcriptional activity in specialized transcription bodies is a hallmark of gene expression in eukaryotic cells. It remains unclear, however, if and how they affect gene expression. Here, we disrupted the formation of two prominent endogenous transcription bodies that mark the onset of zygotic transcription in zebrafish embryos and analysed the effect on gene expression using enriched SLAM-Seq and live-cell imaging. We find that the disruption of transcription bodies results in downregulation of hundreds of genes, providing experimental support for a model in which transcription bodies increase the efficiency of transcription. We also find that a significant number of genes are upregulated, counter to the suggested stimulatory effect of transcription bodies. These upregulated genes have accessible chromatin and are poised to be transcribed in the presence of the two transcription bodies, but they do not go into elongation. Live-cell imaging shows that the disruption of the two large transcription bodies enables these poised genes to be transcribed in ectopic transcription bodies, suggesting that the large transcription bodies sequester a pause release factor. Supporting this hypothesis, we find that CDK9, the kinase that releases paused polymerase II, is highly enriched in the two large transcription bodies. Importantly, overexpression of CDK9 in wild type embryos results in the formation of ectopic transcription bodies and thus phenocopies the removal of the two large transcription bodies. Taken together, our results show that transcription bodies regulate transcription genome-wide: the accumulation of transcriptional machinery creates a favourable environment for transcription locally, while depriving genes elsewhere in the nucleus from the same machinery.

2024-02-05 | GSE235025 | GEO

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