WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer
| Autor: | Qianghua Zhou, Jingtong Zhang, Ruihui Xie, Liang Cheng, Xu Chen, Shengmeng Peng, Yangjie Zhang, Haixia He, Tianxin Lin, Ming Huang, Sen Liu, Jian Huang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Dihydropyridines WDR5 medicine.medical_treatment Survivin Medicine (miscellaneous) Apoptosis Cell Cycle Proteins B7-H1 Antigen Mice 0302 clinical medicine E2F1 RNA Small Interfering Pharmacology Toxicology and Pharmaceutics (miscellaneous) Aurora Kinase A Prostate cancer biology Intracellular Signaling Peptides and Proteins chemoresistance Cell cycle Middle Aged DNA-Binding Proteins Gene Expression Regulation Neoplastic Histone 030220 oncology & carcinogenesis Gene Knockdown Techniques OICR-9429 PC-3 Cells medicine.drug Research Paper PD-L1 Mice Nude Antineoplastic Agents Protein Serine-Threonine Kinases 03 medical and health sciences Cell Line Tumor Proto-Oncogene Proteins medicine Animals Humans Cyclin B1 Aged Cell Proliferation Cisplatin Biphenyl Compounds Prostatic Neoplasms Immunotherapy 030104 developmental biology Drug Resistance Neoplasm Cancer research biology.protein H3K4me3 Tumor Escape Chromatin immunoprecipitation E2F1 Transcription Factor Neoplasm Transplantation |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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