Synergistic Action of WDR5 and HDM2 inhibitors in SMARCB1-deficient cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA781963 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16987600_1.fastq.gz | Fastqsanger.gz | |||
| SRR16987600_2.fastq.gz | Fastqsanger.gz | |||
| SRR16987601_1.fastq.gz | Fastqsanger.gz | |||
| SRR16987601_2.fastq.gz | Fastqsanger.gz | |||
| SRR16987602_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 48 |
Similar Datasets
Project description:Rhabdoid tumors (RT) are rare and aggressive pediatric tumors that are driven by the loss the tumor suppressor SNF5 (SMARCB1). Here we examine how RT cells respond to small molecule-mediated inhibitors of the “WIN” site of WDR5, a chromatin-associated protein that regulates a specific set of genes linked to protein synthesis. We characterize WDR5 binding in RT cell lines via ChIP-Seq and show that WIN site inhibitor rapidly and comprehensively displaces WDR5 from chromatin in these cells. Using Precision Run On-sequencing (PRO-Seq) we show that WDR5-bound protein synthesis genes are early and direct transcriptional targets of WIN site inhibitor. We also use RNA-Seq to characterize the persistent transcriptional changes in RT lines treated with WIN site inhibitor, and compare these transcriptional effects with those of the HDM2 inhibitor nutlin-3a.
2022-03-03 | GSE189205 | GEO
Project description:Action of WDR5 and HDM2 inhibitors in SMARCB1-deficient cancer cells
| PRJNA724689 | ENA
Project description:Rhabdoid tumors (RT) are rare and aggressive pediatric tumors that are driven by the loss the tumor suppressor SNF5 (SMARCB1). Here we examine how RT cells respond to small molecule-mediated inhibitors of the “WIN” site of WDR5, a chromatin-associated protein that regulates a specific set of genes linked to protein synthesis. We characterize WDR5 binding in RT cell lines via ChIP-Seq and show that WIN site inhibitor rapidly and comprehensively displaces WDR5 from chromatin in these cells. Using Precision Run On-sequencing (PRO-Seq) we show that WDR5-bound protein synthesis genes are early and direct transcriptional targets of WIN site inhibitor. We also use RNA-Seq to characterize the persistent transcriptional changes in RT lines treated with WIN site inhibitor, and compare these transcriptional effects with those of the HDM2 inhibitor nutlin-3a.
2022-03-03 | GSE173207 | GEO
Project description:WDR5 is a highly-conserved nuclear protein that performs multiple scaffolding functions in the context of chromatin. WDR5 is also a promising target for pharmacological inhibition in cancer, with small molecule inhibitors of an arginine-binding pocket of WDR5 (the "WIN" site) showing efficacy against a range of cancer cell lines in vitro. Efforts to understand WDR5, or establish the mechanism of action of WIN site inhibitors, however, are stymied by its many functions in the nucleus, and a lack of knowledge of the conserved gene networks—if any—that are under its control. Here, we have performed comparative genomic analyses to identify the conserved sites of WDR5 binding to chromatin, and the conserved genes regulated by WDR5, across a diverse panel of cancer cell lines. We show that a specific cohort of protein synthesis genes (PSGs) are invariantly bound by WDR5, demonstrate that the WIN site anchors WDR5 to chromatin at these sites, and establish that PSGs are both acute and persistent targets of WIN site blockade. Together, these data reveal that WDR5 plays a predominant transcriptional role in biomass accumulation and reinforce the notion that WIN site inhibitors kill sensitive cancer cells by disrupting protein synthesis homeostasis.
2020-01-17 | GSE136451 | GEO
Project description:SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice. Profiling Smarcb1 dependent gene expression we find genes which are dependent on Smarcb1 expression to be enriched for ECM and cell adhesion functions. We identify Igfbp7, which is related to the insulin-like growth factor binding proteins family, as a downstream target of Smarcb1 transcriptional activity, and show that re-introduction of Igfbp7 alone can hinder tumor development. Two cancer cell lines, 167 and 365, derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice were re-infected with a retro-viral vector for Smarcb1 re-expression or an empty retro-viral vector as control. Total-RNA was collected 3 days post infection so as to enrich for direct targets of Smarcb1 transcriptionaly regulated genes
2013-12-31 | E-GEOD-46017 | biostudies-arrayexpress
Project description:Identifying the mechanism action of SMARCB1 in totally different cell lines. Determine whether it is general role or context dependent role.
2019-10-04 | GSE120831 | GEO
Project description:Active gene transcription requires accessible chromatin. Post-translational modifications of histone proteins modulate accessibility to target genes, a process that is controlled by multiple chromatin modifying enzymes, remodelers and epigenetic reader proteins. Histone H3K4 methylation serves as hallmark of actively transcribed genes and is introduced by histone methyltransferases (HMTs). For proper function of HMT activity, several adaptor proteins are required. One of these proteins is the WD-repeat containing protein 5 (WDR5) that acts as scaffolding component in HMT complexes and that has been associated with controlling transcription factors including MYC and long non-coding RNAs. The wide influence of dysfunctional HMTs complexes and the typically upregulated MYC levels in diverse tumor types has made WDR5 an attractive cancer drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might be an elegant way to target all oncogenic function. In this study, we present the design, synthesis and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds. We show that linker nature and length are essential for successful degradation and strongly influences the degradation rate. In the presented datasets, we determined the intracellular degradation specificity of the WDR5 PROTACs (8g, 6, 17b, 14). We therefore treated MV4-11 cells with 8g and 17b, the corresponding ligands 6 and 14, or DMSO and quantified the induced degradation using a label free approach.
2022-01-27 | PXD025257 | Pride
Project description:We discovered potent small molecule inhibitors against the WIN site of WDR5. These inhibitors selectively block the proliferation of mammalian cells carrying fusions of the MLL1 oncogene. Here, we show that these inhibitors result in the rapid displacement of WDR5 from chromatin in both sensitive (MV4:11) and non-sensitive (K562) cell lines, induce early changes in the distribution of active polymerases at a subset of WDR5-bound genes, and induce global transcript changes that are consistent with induction of the tumor suppressor p53.
2019-03-12 | GSE115377 | GEO
Project description:Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1-family-mediated Lys4 methylation of histone H3, associated with positive regulation of transcription. Genetic and pharmacologic inhibition of WDR5 reduced growth and self-renewal of CSCs as well as CSC-mediated tumor growth. Further, WDR5 inhibitors blocked WRAD complex assembly, reduced H3K4 trimethylation, and inhibited tumor growth. These findings highlight the role of WDR5 and the WRAD complex for maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.
2023-01-26 | GSE199110 | GEO