Altered expression of genes in WDR5 knockdown
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE59132 | GEO | 2015/02/09
SECONDARY ACCESSION(S): PRJNA254480
REPOSITORIES: GEO
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Project description:WDR5 (WD repeat domain 5) plays an important role in the epigenetic regulation of gene transcription, involing in regulation of embryonic stem cell and cancer cell.Bladder cancer is one of the most common cancers that cause approximately 150,000 deaths per year worldwide.The goal of this study is to identify the target genes of WDR5 in bladder cancer.Our results inditcate that the genes regulated by WDR5 involved in a variety of biological functions, such as proliferation and anti-apoptosis. Bladder cancer cell line UM-UC-3 was transfected with the contol siRNA or two different WDR5 siRNA for 48h. The RNA of the transfected cells was extracted and hybridized on Affymetrix microarrays. We indentified the putative target genes of WDR5 in both WDR5 siRNA by comparing the diferent expressed genes among control, si-WDR5-2 and si-WDR5-3. We futher validated the data of microarray in UM-UC-3 and T24 by RT-qPCR and Western bloting.
2015-02-09 | E-GEOD-59132 | biostudies-arrayexpress
Project description:WD repeat domain 5 (WDR5) plays an important role in various biological functions through the epigenetic regulation of gene transcription. However, the oncogenic effect of WDR5 in leukemia remains largely unknown. Here, we found WDR5 expression is increased in leukemia patients. High expression of WDR5 is associated with high risk leukemia; Patients with WDR5 and MLL1 high expression have poor complete remission rate. We further identified the global genomic binding of WDR5 in leukemic cells and found the genomic co-localization of WDR5 binding with H3K4me3 enrichment. Moreover, WDR5 knockdown by shRNA suppresses cell proliferation, induces apoptosis, inhibits the expression of WDR5 targets, and blocks the H3K4me3 enrichment on the promoter of its targets. We also observed the positive correlation of WDR5 expression with these targets in the cohort study of leukemia patients. Our data reveal that WDR5 may have oncogenic effect and WDR5-mediated H3K4 methylation plays an important role in leukemogenesis.
2016-12-30 | GSE72864 | GEO
Project description:Purpose: Metastatic breast cancer remains a major cause of cancer related deaths in women and there are few effective therapies against this advanced disease. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. Here we profile the transcriptome of metastatic breast cancer cells following WDR5 knockdown Methods: RNA-Seq analysis of breast cancer cell lines MDA-MB-231 LM2, BoM, BrM3 Results: We identified that WDR5 directly controls the expression of ribosomal genes. Conclusions: We found that WDR5 is a potential target in breast cancer metastasis
2022-08-31 | GSE196666 | 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:The core subunit of the COMPASS-like complex, WD Repeat Domain 5 (WDR5) has a prominent role in reprogramming and Epithelial-to-Mesenchymal transition (EMT) in different tumor types. Our evidences support a model in which WDR5 is prominent for EMT and metastasis dissemination in breast cancer patient-derived xenografts and cell lines. Moreover, WDR5 silencing abrogates TGFB pathway activation and reverts mesenchymal into epithelial phenotype, by inhibiting transcription of main master regulators of EMT (CDH2, TWIST1, SNAI1, SNAI2 and ZEB1). Our data suggest that WDR5 inhibition may be a successful approach to prevent progression of metastatic BC.
2019-12-17 | GSE113279 | GEO
Project description:The core subunit of the COMPASS-like complex, WD Repeat Domain 5 (WDR5) has a prominent role in reprogramming and Epithelial-to-Mesenchymal transition (EMT) in different tumor types. Our evidences support a model in which WDR5 is prominent for EMT and metastasis dissemination in breast cancer patient-derived xenografts and cell lines. Moreover, WDR5 silencing abrogates TGFB pathway activation and reverts mesenchymal into epithelial phenotype, by inhibiting transcription of main master regulators of EMT (CDH2, TWIST1, SNAI1, SNAI2 and ZEB1). Our data suggest that WDR5 inhibition may be a successful approach to prevent progression of metastatic BC.
2019-12-17 | GSE113288 | GEO
Project description:The core subunit of the COMPASS-like complex, WD Repeat Domain 5 (WDR5) has a prominent role in reprogramming and Epithelial-to-Mesenchymal transition (EMT) in different tumor types. Our evidences support a model in which WDR5 is prominent for EMT and metastasis dissemination in breast cancer patient-derived xenografts and cell lines. Moreover, WDR5 silencing abrogates TGFB pathway activation and reverts mesenchymal into epithelial phenotype, by inhibiting transcription of main master regulators of EMT (CDH2, TWIST1, SNAI1, SNAI2 and ZEB1). Our data suggest that WDR5 inhibition may be a successful approach to prevent progression of metastatic BC.
2019-12-17 | GSE113283 | GEO
Project description:WD repeat domain 5 (WDR5), a chromatin regulator associated with MLL complex and MYC oncoproteins, was shown to be critical for oncogenesis in human cancers and represents an attractive drug target. Inhibitors for targeting protein-protein interaction interfaces (PPIs) within WDR5 were developed; however, they inhibited only a part of WDR5-mediated functional interactions, exerting rather limited antitumor effects. We report a cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) of WDR5, MS40, which is capable of selectively degrading cellular WDR5 and the well-established IMiDs:CRBN targets such as Ikaros (IKZF1). MS40-induced WDR5 degradation caused disassociation of MLL complex off chromatin, resulting in a decrease of global H3K4me2. Transcriptomic profiling revealed that gene targets of WDR5 and IMiDs:CRBN were both repressed by MS40. In MLL-rearranged acute leukemias, which exhibit high IKZF1 expression and IKZF1 dependency, co-suppression of WDR5 and IKZF1/3 by MS40 is superior at suppressing tumor growth not only to WDR5 PPI inhibitors but also to a matched VHL-based WDR5 PROTAC, MS169, which selectively targets WDR5 only. Furthermore, MS40 suppressed growth of primary leukemia patient cells in vitro and patient-derived xenografts (PDX) in vivo. Collectively, we report the discovery of a dual WDR5 and Ikaros degrader as anti-cancer therapeutic.
2022-05-15 | GSE195729 | GEO
Project description:WD repeat domain 5 (WDR5), a chromatin regulator associated with MLL complex and MYC oncoproteins, was shown to be critical for oncogenesis in human cancers and represents an attractive drug target. Inhibitors for targeting protein-protein interaction interfaces (PPIs) within WDR5 were developed; however, they inhibited only a part of WDR5-mediated functional interactions, exerting rather limited antitumor effects. We report a cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) of WDR5, MS40, which is capable of selectively degrading cellular WDR5 and well-established imide:CRBN targets such as Ikaros (IKZF1). MS40-induced WDR5 degradation caused disassociation of MLL complex off chromatin, resulting in a decrease of global H3K4me2. Transcriptomic profiling also revealed targets of both WDR5 and imide:CRBN to be repressed by MS40. In MLL-rearranged acute leukemias, which exhibit high IKZF1 expression and IKZF1 dependency, co-suppression of WDR5 and IKZF1/3 by MS40 is superior at suppressing tumor growth not only to WDR5 PPI inhibitors but also to a VHL-based WDR5 PROTAC, MS169, which selectively targets WDR5 only. Furthermore, MS40 suppressed growth of primary leukemia patient cells in vitro and patient-derived xenografts (PDX) in vivo. Collectively, we report the discovery of a dual WDR5 and Ikaros degrader as anti-cancer therapeutic.
2022-05-15 | GSE175547 | GEO
Project description:WD repeat domain 5 (WDR5), a chromatin regulator associated with MLL complex and MYC oncoproteins, was shown to be critical for oncogenesis in human cancers and represents an attractive drug target. Inhibitors for targeting protein-protein interaction interfaces (PPIs) within WDR5 were developed; however, they inhibited only a part of WDR5-mediated functional interactions, exerting rather limited antitumor effects. We report a cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) of WDR5, MS40, which is capable of selectively degrading cellular WDR5 and well-established imide:CRBN targets such as Ikaros (IKZF1). MS40-induced WDR5 degradation caused disassociation of MLL complex off chromatin, resulting in a decrease of global H3K4me2. Transcriptomic profiling also revealed targets of both WDR5 and imide:CRBN to be repressed by MS40. In MLL-rearranged acute leukemias, which exhibit high IKZF1 expression and IKZF1 dependency, co-suppression of WDR5 and IKZF1/3 by MS40 is superior at suppressing tumor growth not only to WDR5 PPI inhibitors but also to a VHL-based WDR5 PROTAC, MS169, which selectively targets WDR5 only. Furthermore, MS40 suppressed growth of primary leukemia patient cells in vitro and patient-derived xenografts (PDX) in vivo. Collectively, we report the discovery of a dual WDR5 and Ikaros degrader as anti-cancer therapeutic.
2022-05-15 | GSE175544 | GEO