Targeting WD repeat domain 5 enhances chemosensitivity and inhibits proliferation and programmed death-ligand 1 expression in bladder cancer
| Autor: | Lixuan Liu, Ruihui Xie, Shengmeng Peng, Yangjie Zhang, Tianxin Lin, Yuelong Chen, Qianghua Zhou, Ming Huang, Wen Dong, Jinli Han, Xu Chen, Jian Huang, Liang Cheng, Jingtong Zhang, Keji Xie |
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| Rok vydání: | 2021 |
| Předmět: |
PD-L1
Male 0301 basic medicine Dihydropyridines Cancer Research medicine.medical_treatment Antineoplastic Agents Apoptosis Target therapy B7-H1 Antigen Metastasis 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Humans Molecular Targeted Therapy Viability assay skin and connective tissue diseases Chemosensitivity RC254-282 Cell Proliferation Cisplatin biology Chemistry Research Bladder cancer Biphenyl Compounds Intracellular Signaling Peptides and Proteins Neoplasms. Tumors. Oncology. Including cancer and carcinogens WDR5 inhibitor Immunotherapy Cell cycle medicine.disease Up-Regulation 030104 developmental biology Urinary Bladder Neoplasms Oncology 030220 oncology & carcinogenesis OICR-9429 Cancer research FOXM1 biology.protein Female medicine.drug |
| Zdroj: | Journal of Experimental & Clinical Cancer Research : CR Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-17 (2021) |
| ISSN: | 1756-9966 |
| DOI: | 10.1186/s13046-021-01989-5 |
| Popis: | Background Chemotherapy 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. Methods We 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. Results First, 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. Conclusions Our 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. |
| Databáze: | OpenAIRE |
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