WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer
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ABSTRACT:
PROVIDER: PRJNA699435 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR13627107_1.fastq.gz | Fastqsanger.gz | |||
| SRR13627107_2.fastq.gz | Fastqsanger.gz | |||
| SRR13627108_1.fastq.gz | Fastqsanger.gz | |||
| SRR13627108_2.fastq.gz | Fastqsanger.gz | |||
| SRR13627109_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Advanced prostate cancer (PCa) has limited treatment regimens and shows low response to chemotherapy and immunotherapy, leading to poor prognosis. Histone modification is a vital mechanism of gene expression and a promising therapy target. In this study, we characterized WD repeat domain 5 (WDR5), a regulator of histone modification, and explored its potential therapeutic value in PCa. Experimental Design: We characterized specific regulators of histone modification, based on TCGA data. The expression and clinical features of WDR5 were analyzed in two dependent cohorts. The functional role of WDR5 was further investigated with siRNA and OICR-9429, a small molecular antagonist of WDR5, in vitro and in vivo. The mechanism of WDR5 was explored by RNA-sequencing and chromatin immunoprecipitation (ChIP). Results: WDR5 was overexpressed in PCa and associated with advanced clinicopathological features, and predicted poor prognosis. Both inhibition of WDR5 by siRNA and OICR-9429 could reduce proliferation, and increase apoptosis and chemosensitivity to cisplatin in vitro and in vivo. Interestingly, targeting WDR5 by siRNA and OICR-9429 could block IFN-γ-induced PD-L1 expression in PCa cells. Mechanistically, we clarified that some cell cycle, anti-apoptosis, DNA repair and immune related genes, including AURKA, CCNB1, E2F1, PLK1, BIRC5, XRCC2 and PD-L1, were directly regulated by WDR5 and OICR-9429 in H3K4me3 and c-Myc dependent manner. Conclusions: These data revealed that targeting WDR5 suppressed proliferation, enhanced apoptosis, chemosensitivity to cisplatin and immunotherapy in PCa. Therefore, our findings provide insight into OICR-9429 is a multi-potency and promising therapy drug, which improves the antitumor effect of cisplatin or immunotherapy in PCa.
| S-EPMC7978315 | biostudies-literature
Project description:Our results demonstated that OICR-9429 a inhibitor of WDR5, could supress the proliferation and chemo-resistance of prostate cancer cells. To explore the molecular mechanism underlying OICR-9429-induced WDR5 inhibition in Prostate cancer cells, we conducted a genome-wide RNA-sequencing to compare gene expression profiles between OICR-9429 treated DU145, PC3-3 cells and their control cells
2021-07-01 | GSE166136 | GEO
Project description:BackgroundChemotherapy and/or immunotherapy are first-line treatments for advanced muscle-invasive bladder cancer (BCa), but the unsatisfactory objective response rate to these treatments yields poor 5-year patient survival. Discovery of therapeutic targets essential for BCa maintenance is critical to improve therapy response in clinic. This study evaluated the role of targeting WD repeat domain 5 (WDR5) with the small molecule compound OICR-9429 and whether it could be used to treat bladder cancer.MethodsWe analysed the expression and clinical prognosis of WDR5 in a TCGA cohort. The pharmacological role of OICR-9429 was further investigated in vitro and in vivo. RNA sequencing, western blot, and chromatin immunoprecipitation (ChIP) were utilized to explored the mechanism underlying OICR-9429-induced WDR5 inhibition.ResultsFirst, we found that WDR5 expression was upregulated in BCa and was associated with histologic grade, metastasis status, histologic subtype, and molecular subtype. High WDR5 expression level was also correlated with shorter overall survival (OS) in BCa. The WDR5 inhibitor OICR-9429 reduced cell viability by decreasing H3K4me3 levels but not WDR5 levels in T24, UM-UC-3, and TCCSUP BCa cells. OICR-9429 suppressed the proliferation of BCa cells by blocking the G1/S phase transition. Next, OICR-9429 enhanced apoptosis and chemosensitivity to cisplatin in BCa cells. In addition, OICR-9429 independently inhibited the motility and metastatic behaviour of BCa cells. In vivo experiments further revealed that OICR-9429 suppressed tumour growth, enhanced chemosensitivity, and reduced the toxicity of cisplatin in BCa. Notably, WDR5 was positively correlated with programmed death-ligand 1 (PD-L1) expression, and OICR-9429 suppressed immune evasion by blocking PD-L1 induced by IFN-γ. Mechanistically, some cell cycle-, antiapoptosis-, DNA repair-, metastasis-, and immune evasion-related genes, including BIRC5, XRCC2, CCNB1, CCNE2, PLK1, AURKA, FOXM1, and PD-L1 were identified to be directly regulated by OICR-9429 in a H3K4me3-dependent manner.ConclusionsOur novel finding is that the WDR5 inhibitor, OICR-9429, suppressed proliferation, metastasis and PD-L1-based immune evasion while enhancing apoptosis and chemosensitivity to cisplatin in BCa by blocking the WDR5-MLL complex mediating H3K4me3 in target genes. Hence, our findings offer insight into a multipotential anticancer compound, OICR-9429, which enhances the antitumour effect of cisplatin or immunotherapy in BCa.
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Project description:Programmed Cell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation and Activation
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Project description:Structure-Based Discovery of Potent WD Repeat Domain 5 Inhibitors that Demonstrate Efficacy and Safety in Preclinical Animal Models
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Project description:WD repeat domain 5 (WDR5) is a core scaffolding component of many multi-protein complexes that perform a variety of critical chromatin-centric processes in the nucleus. WDR5 is component of the mixed lineage leukemia MLL/SET complex and localizes MYC to chromatin tumor-critical target genes. Overexpression of WDR5 promotes oncogenesis in a variety of human cancers that are often associated with poor prognoses. Thus, WDR5 has been recognized as an attractive therapeutic target for treating both solid and hematological tumors. Previously, small-molecule WDR5 WIN-site inhibitors and WDR5 degraders have demonstrated robust in vitro cellular efficacy in cancer cell lines and established the therapeutic potential of WDR5. However, these agents have not demonstrated significant in vivo efficacy at pharmacologically relevant doses by oral administration in animal disease models. We have discovered WDR5 WIN-site inhibitors that feature bicyclic heteroaryl P7 units through structure-based design and address the limitations of our previous series of small-molecule inhibitors. Importantly, our new lead compounds exhibit enhanced on-target potency, excellent oral pharmacokinetic (PK) profiles, and potent dose-dependent in vivo efficacy in a mouse MV4:11 subcutaneous xenograft model by oral dosing. Furthermore, these in vivo probes show excellent tolerability under a repeated high dose regimen in rodents to demonstrate the safety of the WDR5 WIN site inhibition mechanism. Collectively, our results provide strong support for WDR5 WIN-site inhibitors to be utilized as potential anticancer therapeutics.
2022-10-01 | GSE203101 | GEO
Project description:Thomasclavelia ramosa strain:WD-I2 Genome sequencing and assembly
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Project description:We identified differentially expressed genes in response to single and double ligand treatments (LPS, IFG, 2MA, LPS plus 2MA, and LPS plus IFG). The majority of the regulated transcripts responded additively to dual ligand treatment. However, a significant fraction responded in a non-additive fashion. Several cytokines showing non-additive transcriptional responses to dual ligand treatment also showed non-additive protein production/secretion responses in separate experiments. Many of the genes with non-additive responses to LPS plus 2MA showed enhanced responses and encoded pro-inflammatory proteins. On the other hand, LPS plus IFG appeared to induce both non-additive enhancement and non-additive attenuation of gene expression. The affected genes were associated with a variety of biological functions. These experiments reveal both dependent and independent regulatory pathways and further analyses may point out the specific nature of the regulatory interactions. Keywords = Lipopolysaccharide Keywords = Interferon-gamma Keywords = 2-Methyl-thio-ATP Keywords = Dual Ligand Effects Keywords = Gene Expression Keywords = RAW 267.4 Keywords = Macrophage Keywords: repeat sample
2004-10-23 | GSE1863 | GEO
Project description:Interleukin (IL)-27 is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T cells rapidly induced by IL-27. We found that IL-27 priming of naïve T cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)1-dependent manner. When co-cultured with naïve CD4+ T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans through a PD-1-PD-L1 interaction. In vivo, co-administration of naïve TCR transgenic T cells (2D2 T cells) with IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4+ T cells can restrict differentiation of Th17 cells in trans. The roles of IL-6 and IL-27 in naïve CD4+ T cells was investigated by comparing global gene expression by Affymetrix Mouse Genome 430 2.0 Arrays. The functional outcome of STAT proteins was further evaluated by profiling gene expression changes between WT and STAT-deficient T cells in naïve CD4+ T cells with specific stimulation. All condition were done in biological triplicate.
2012-06-30 | E-GEOD-38375 | biostudies-arrayexpress