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CDK7 Inhibition by THZ1 Suppresses Cancer Stemness in both Chemonaïve and Chemoresistant Urothelial Carcinoma via the Hedgehog Signaling Pathway

ABSTRACT: CDK7 Inhibition by THZ1 Suppresses Cancer Stemness in both Chemonaïve and Chemoresistant Urothelial Carcinoma via the Hedgehog Signaling Pathway

PROVIDER: PRJNA690137 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13375492_1.fastq.gz	Fastqsanger.gz
	SRR13375492_2.fastq.gz	Fastqsanger.gz
	SRR13375493_1.fastq.gz	Fastqsanger.gz
	SRR13375493_2.fastq.gz	Fastqsanger.gz

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CDK7 Inhibition by THZ1 Suppresses Cancer Stemness in both Chemonaïve and Chemoresistant Urothelial Carcinoma via the Hedgehog Signaling Pathway

Project description:THZ1 inhibits cancer stemness via Hedgehog pathway.

2021-03-21 | GSE164370 | GEO

CDK7 inhibitor THZ1 induces the cell apoptosis of B-cell acute lymphocytic leukemia by perturbing cellular metabolism

Project description:Purpose:CDK7 is a potential drug target for the treatment of tumors. THZ1 is the first selective and covalent CDK7 inhibitor, which shows anti-tumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis. However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains unclear. To address this question, we collected THZ1- and DMSO-treated cells for RNA sequencing Methods:Nalm6 cells were seeded at a density of 1× 10e6 cells/ml and treated with 500nm THZ1or DMSO for 24h. Results:THZ1 perturbed the cellular metabolic pathways of B-ALL cells in vitro.

2021-02-20 | GSE167099 | GEO

THZ1-induced transcriptional changes in SMO inhibitor responsive and resistant mouse hedgehog-driven medulloblastoma cells

Project description:Purpose: To assess THZ1-induced global changes of transcriptome of Hh-driven cancer Methods: SMB56 or SMB56-shSufu cells were mouse hedgehog-driven medulloblastoma cell lines that are either responsive or resistant to SMO inhibitor (GDC-0449). They were treated with 0.1 uM THZ1 or DMSO for 8 hours. 1 uM GDC-0449 treated SMB56 cells were included as control. Gene expression profiles were generated by RNAseq, in duplicate, using Hiseq3000. The RNAseq reads were mapped to the hg19 reference genome using STAR (v2.5.3a). Expression levels for each sample were quantified to FPKM using Cufflinks (v2.2.1). Differential expression analysis was carried out using R package DESeq2 (v1.20.0) Results: Compared to GDC-0449 treatment in SMB56 cells, THZ1 induced a robust global transcriptional downregulation in both SMB56 and SMB56-shSufu cells. When we compared the top 2000 significantly downregulated genes between THZ1-treated SMB56 and SMB56-shSufu cells, we found they had ~70% in common. GSEA reveals Hh-target genes are enriched in DMSO treated cells versus THZ1-treated ones. Conclusions: CDK7 inhibition induced a robust and similar transcriptional downregulation in both SMB56 and SMB56-shSufu cells, with preferential targeting of Hh pathway transcriptional output.

2019-05-01 | GSE130485 | GEO

THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors

Project description:Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signaling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.

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The CDK7 Inhibitor THZ1 Alters RNA Polymerase Dynamics at the 5’ and 3’ Ends of Genes

Project description:The t(8;21) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML). We found that t(8;21) AML were extremely sensitive to THZ1, which triggered apoptosis after only 4 hr. We used precision nuclear run-on transcription sequencing (PROseq) to define the global effects of THZ1 and other CDK inhibitors on RNA polymerase II dynamics. Inhibition of CDK7 using THZ1 caused wide-spread loss of promoter-proximal paused RNA polymerase. This loss of 5’ pausing was associated with accumulation of polymerases in the body of a large number of genes. However, there were modest effects on genes regulated by “super-enhancers”. At the 3’ ends of genes, treatment with THZ1 suppressed RNA polymerase “read through” at the end of the last exon, which resembled a phenotype associated with a mutant RNA polymerase with slower elongation rates. Consistent with this hypothesis, polyA site-sequencing (PolyA-seq) did not detect differences in polyA sites after THZ1 treatment. PROseq analysis after short treatments with THZ1 suggested that these 3’ effects were due to altered CDK7 activity at the 5’ end of long genes, and were likely to be due to slower rates of elongation.

2019-02-11 | GSE102243 | GEO

RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of mouse hearts to transverse aortic artery constriction (TAC)

Project description:RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of mouse hearts to TAC

2022-04-25 | GSE151254 | GEO

RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of neonatal rat ventricular myocytes (NRVM) to adrenergic receptor agonist phenylephrine (PE)

Project description:RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of NRVM to adrenergic receptor agonist PE

2022-04-25 | GSE151253 | GEO

RNA polymerase II (RNAPII) ChIP-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of neonatal rat ventricular myocytes (NRVM) to adrenergic receptor agonist phenylephrine (PE)

Project description:RNA polymerase II (RNAPII) ChIP-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of NRVM to adrenergic receptor agonist PE

2022-04-25 | GSE151252 | GEO

Inhibition of gene transcription after THZ1 treatment in HeLa

Project description:To explore the transcriptional inhibition of the CDK7 inhibitor THZ1 in cervical cancer cells, we used gene expression miceoarray analysis to detect the gene expression profiles after THZ1 treatment in HeLa compared with negative control（DMSO）. HeLa was trreated with 100 nM THZ1 or DMSO, and total RNA was extracted after treatment for 6 hours. Microarray analysis showed that massive oncogene transcripts, especially those associated with tumorigenesis, were preferential suppressed after THZ1 treatment.

2019-05-10 | GSE125543 | GEO

Differential gene expression analysis of MYCN-amplified neuroblastoma cells after THZ1 and TKI combination therapy.

Project description:The CDK7 inhibitor THZ1 has been shown to suppress MYCN gene transcription but not cause significant cell death as a single agent. The tyrosine kinase inhibitors (TKIs) ponatinib and lapatinib were found to exert synergistic anti-cancer effects in combination with the CDK7 inhibitor THZ1, on MYCN amplified neuroblastoma cell lines.

2020-03-20 | GSE128649 | GEO

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