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The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis

ABSTRACT: The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis

PROVIDER: PRJNA742070 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14933200.fastq.gz	Fastqsanger.gz
	SRR14933201.fastq.gz	Fastqsanger.gz
	SRR14933202.fastq.gz	Fastqsanger.gz
	SRR14933203.fastq.gz	Fastqsanger.gz
	SRR14933204.fastq.gz	Fastqsanger.gz

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The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis

Project description:Melanoma accounts for the majority of all skin cancer-related deaths and only 1/3rd of melanoma patients with distal metastasis survive beyond five years. However, current therapies including BRAF/MEK targeted therapies or immunotherapies only benefit a subset of melanoma patients due to the emergence of intrinsic or extrinsic resistance mechanisms. Effective treatment of melanoma will thus require new and more effective therapeutic agents. Towards the goal of identifying new therapeutic agents, we conducted an unbiased, druggable epigenetic drug screen using a library of 32 epigenetic inhibitors obtained from the Structural Genome Consortium that targets proteins encoding for epigenetic regulators. This chemical genetic screening identified TP-472, which targets bromodomain-7/9, as the strongest inhibitor of melanoma growth in both short- and long-term survival assays and in mouse models of melanoma tumor growth. Mechanistically, using a transcriptome-wide mRNA sequencing profile we identified TP-472 treatment downregulates genes encoding various extracellular matrix (ECM) proteins, including integrins, collagens, and fibronectins. Reactome-based functional pathway analyses revealed that many of the ECM proteins are involved in extracellular matrix interactions required for cancer cell growth and proliferation. TP-472 treatment also upregulated several pro-apoptotic genes that can inhibit melanoma growth. Collectively, our results identify BRD7/9 inhibitor TP-472 as a potentially useful therapeutic agent for melanoma therapy.

2021-12-23 | GSE179079 | GEO

The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis.

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Agrobacterium tumefaciens strain:SEMIA 472 | isolate:SEMIA 472

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BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma drives human dilated cardiomyopathy

Project description:By using a small molecule compound library targeting epigenetic enzymes we have identified BRD9 enzyme for eliminating CSCs. Genomic and proteomic studies revealed that BRD9/BAF complex regulates expression of stemness factors and chemoresistance by cooperating with TGFβ/Activin-SMAD2/3 signalling pathway. Chemical inhibition and genetic loss of function of BDR9 blocks the self-renewal of CSCs, reduces CSC invasiveness and resensitizes PDAC CSCs to conventional therapies. Analyses of chromatin architecture showed that BRD9 regulates the 3D chromatin looping between promoters and enhancers of stemness genes and EMT regulators in CSCs. BRD9 inhibition abrogated tumour formation in mice and eliminated CSCs in tumours from pancreatic cancer patients. Collectively, we uncovered BRD9 enzyme as an attractive therapeutic target for re-sensitizing and eliminating CSCs in pancreatic cancer patients.

2024-01-01 | GSE222952 | GEO

Genome-wde mapping of BRD9 binding sites and gene expression changes upon BRD9 knockdown

Project description:Leukemia is characterized by genetic and epigenetic mutations resulting in selection of cancer cells, which are unable to differentiate. While genetic alterations are difficult to target, the epigenome is intrinsically dynamic and readily offers new therapeutic strategies. Thus, identifying cancer-specific context-dependent targets and unraveling their biological function may open up new therapeutic perspectives. Here, we identify bromodomain-containing protein 9 (BRD9) as a critical target required in acute myeloid leukemia (AML). We show that BRD9 is overexpressed in AML cells including ex vivo primary blasts compared to CD34+ cells. By targeting BRD9 expression in AML, we observed an alteration in proliferation and survival, ultimately resulting in the induction of apoptosis. Intriguingly, genome-wide profiling revealed that BRD9 binds enhancer regions in a cell type-specific manner, regulating cell type-related processes. We unveil a novel BRD9-sustained STAT5 pathway activation via regulation of SOCS3 expression levels. Our findings identify a previously undescribed BRD9-STAT5 axis as critical for leukemia maintenance, suggesting BRD9 as a potential therapeutic target.

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Cutibacterium acnes strain:TP-CU426

Project description:TP-CU426

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Thlaspi arvense cultivar:2020-M2-472

Project description:Thlaspi arvense 2020-M2-472 Resequencing

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BRD9 regulates leukemic cell survival via STAT5 pathway inhibition

Project description:Leukemia is characterized by genetic and epigenetic mutations resulting in selection of cancer stem cells, which are unable to differentiate. While genetic alterations are difficult to target, the epigenome is intrinsically dynamic and readily offers new therapeutic strategies. Thus, identifying cancer-specific context-dependent targets and unraveling their biological function may open up new therapeutic perspectives. Here, we identify bromodomain-containing protein 9 (BRD9) as a critical target required in acute myeloid leukemia (AML). We show that BRD9 is overexpressed in AML cells including ex vivo primary blasts compared to CD34+. By targeting BRD9 expression in AML, we observed an alteration in proliferation and survival, ultimately resulting in the induction of apoptosis. Intriguingly, genome-wide profiling revealed that BRD9 binds enhancer regions in a cell type-specific manner, regulating cell type-related processes. We unveil a novel BRD9-sustained STAT5 pathway activation via regulation of SOC3 expression levels. Our findings identify a previously undescribed BRD9-STAT5 axis as critical for leukemia maintenance, suggesting BRD9 as a potential therapeutic target.

2019-11-11 | PXD013245 | Pride

Phage TP-84

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Panicum virgatum cultivar:AP13xWBC3xDAC6xVS16 - 472

Project description:Panicum virgatum AP13xWBC3xDAC6xVS16 - 472 - Mapping Population genome sequencing

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