ArticleJournal of experimental & clinical cancer research : CR2021
Targeting WD repeat domain 5 enhances chemosensitivity and inhibits proliferation and programmed death-ligand 1 expression in bladder cancer.
Article in Journal of experimental & clinical cancer research : CR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
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Who cites it
59 citing papers in PubMed, 1 synthesis or guideline pooled it, 93 citations in OpenAlex.
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- Decoding WDR5-Mediated Interactions in Gliomas: Implications for Targeted Therapy.Medicinal research reviews · 2026Review
- Lactate-induced H3K4me3 histone mark promotes PLOD1-driven prostate cancer invasion.Cell death & disease · 2026Article
- The role of the WD40-repeat protein family in cancer.Molecular cancer · 2026Review
- A smart gene circuit for precise regulation of tumor cell behavior.Synthetic and systems biotechnology · 2026Article
- MAT2A promotes atherosclerotic plaque vulnerability by mediating epigenetic reprogramming of macrophages.Nature communications · 2025Article
- Menin facilitates the cell proliferation of bladder cancer via modulating the TFAP2C/β-catenin axis.Genes & diseases · 2025Article
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics.Nature communications · 2025Article
- Glycyrrhizin enhances the antitumor activity of cisplatin in non‑small cell lung cancer cells by influencing DNA damage and apoptosis.Oncology letters · 2025Article
- Targeting WDR5/ATAD2 signaling by the CK2/IKAROS axis demonstrates therapeutic efficacy in T-ALL.Blood · 2025Article
- Signatures of H3K4me3 modification predict cancer immunotherapy response and identify a new immune checkpoint-SLAMF9.Respiratory research · 2025Article
- Hypoxia-Induced Histone Lactylation Drives Cisplatin Resistance in Bladder Cancer by Promoting RBM15-Dependent mResearch (Washington, D.C.) · 2025Article
- Sanguinarine identified as a natural dual inhibitor of AURKA and CDK2 through network pharmacology and bioinformatics approaches.Scientific reports · 2024Article
- OncogenicMedComm · 2024Article
- Targeting histone modifiers in bladder cancer therapy - preclinical and clinical evidence.Nature reviews. Urology · 2024Review
- Article
- H3K4me3-Mediated FOXJ2/SLAMF8 Axis Aggravates Thrombosis and Inflammation in β2GPI/Anti-β2GPI-Treated Monocytes.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Synovial Sarcoma Chromatin Dynamics Reveal a Continuum in SS18:SSX Reprograming.bioRxiv : the preprint server for biology · 2024Article
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.