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Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

ABSTRACT: Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

PROVIDER: PRJNA559171 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9920760.fastq.gz	Fastqsanger.gz
	SRR9920761.fastq.gz	Fastqsanger.gz
	SRR9920762.fastq.gz	Fastqsanger.gz
	SRR9920763.fastq.gz	Fastqsanger.gz
	SRR9920764.fastq.gz	Fastqsanger.gz

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Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

Project description:We report the global gene expression effects in TSC-deficient and TSC wild type cells after treatemnet with. CDK7 inhibitor(THZ1), we performed RNA-Seq on TSC1-null HCV.29 cells and TSC1-intact HCV.29 cells treated with 30nM THZ1, and with 100nM THZ1, for 6 hours. Many genes showed marked changes in expression in comparison with control untreated cells. Furthermore, 1128 genes showed > 5-fold lower expression in 30nM THZ1-treated TSC1-null HCV.29 cells compared with 30nM THZ1-treated TSC1-intact HCV.29 cells.

2019-08-08 | GSE135527 | GEO

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion.

Project description:Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces glutathione levels and increases reactive oxygen species due to reduced expression of NRF2 and glutathione biosynthesis genes. Treatment of both Tsc2+/ - mice and a TSC1-null bladder cancer xenograft model with a CDK7 inhibitor showed marked reduction in tumor volume and absence of regrowth in the xenograft model. These results suggest that CDK7 inhibition is a promising therapeutic approach for treatment of TSC-associated tumors and cancers with mutations in either TSC1 or TSC2.

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CDK7-dependent Transcriptional Addiction in Triple-Negative Breast Cancer (Microarray)

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

CDK7-dependent Transcriptional Addition in Basal-like Breast Cancer

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

Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection

Project description:Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection

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A novel covalent inhibitor of CDK7 synergizes with Venetoclax in acute myeloid leukemia

Project description:To assess the synergistic effects of CDK7 inhibitor with Venetoclax, we performed RNA sequencing and gene set enrichment analysis using Venetoclax sensitive and resistant model systems. RNA-sequencing from paired Venetoclax-sensitive and Venetoclax-resistant cells treated with CDK7 inhibitor showed downregulation of genes involved in proliferation and apoptosis. CDK7 inhibitor induces apoptosis in AML cells and combined treatment with Venetoclax led to synergistic effects in overcoming resistance.

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Project description:CDK7 phosphorylates the RNA polymerase II (pol II) CTD and activates the P-TEFb- associated kinase, CDK9, but its regulatory roles remain obscure. Using human CDK7 analog-sensitive (CDK7as) cells, we observed reduced capping enzyme recruitment, increased pol II promoter-proximal pausing, and defective termination at gene 3'-ends upon CDK7 inhibition. We also found that CDK7 regulates chromatin modifications downstream of transcription start sites. H3K4me3 spreading was restricted at gene 5'-ends and H3K36me3 was displaced toward gene 3'-ends in CDK7as cells. Together, these results implicate a CDK7-dependent "CTD code" that regulates epigenetic marks in addition to RNA processing and pol II pausing.

2017-08-01 | GSE100040 | GEO

GDF15-GFRAL orchestrates glutathione synthesis via NRF2-elicited GCLC activation to impedes cuproptosis

Project description:GDF15-GFRAL orchestrates glutathione synthesis via NRF2-elicited GCLC activation to impedes cuproptosis

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Effect of liver-specific deletion of Gclc, Nrf2, and Gclc-Nrf2 on the liver

Project description:The rate-limiting step in glutathione (GSH) synthesis is controlled by glutamate-cysteine ligase catalytic subunit. GSH is reported to buffer oxidative stress. In the absence of GSH, the antioxidant transcription factor Nrf2 is reported to be stabilized. The liver has the highest levels of GSH, but its impact on liver homeostasis is unclear. To investigate this, we induced a liver-specific deletion of Gclc (Gclc f/f), Nrf2 (Nrf2 f/f), or Gclc-Nrf2 (Gclc f/f Nrf2 f/f) by injecting my via tail-vein with AAV-TBG-Cre, which induces recombination specifically in hepatocytes.

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CDK7-dependent Transcriptional Addiction in Triple-Negative Breast Cancer (Microarray)

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