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WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer.
- Source :
-
Theranostics [Theranostics] 2021 Mar 04; Vol. 11 (10), pp. 4809-4824. Date of Electronic Publication: 2021 Mar 04 (Print Publication: 2021). - Publication Year :
- 2021
-
Abstract
- 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.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.<br /> (© The author(s).)
- Subjects :
- Aged
Animals
Apoptosis drug effects
Aurora Kinase A genetics
Aurora Kinase A metabolism
B7-H1 Antigen genetics
B7-H1 Antigen metabolism
Biphenyl Compounds pharmacology
Cell Cycle Proteins genetics
Cell Cycle Proteins metabolism
Cell Line, Tumor
Cell Proliferation drug effects
Cyclin B1 genetics
Cyclin B1 metabolism
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Dihydropyridines pharmacology
E2F1 Transcription Factor genetics
E2F1 Transcription Factor metabolism
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Male
Mice
Mice, Nude
Middle Aged
Neoplasm Transplantation
PC-3 Cells
Prostatic Neoplasms drug therapy
Prostatic Neoplasms metabolism
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins metabolism
RNA, Small Interfering
Survivin genetics
Survivin metabolism
Tumor Escape drug effects
Tumor Escape genetics
Polo-Like Kinase 1
Antineoplastic Agents therapeutic use
Apoptosis genetics
Cell Proliferation genetics
Cisplatin therapeutic use
Drug Resistance, Neoplasm genetics
Intracellular Signaling Peptides and Proteins genetics
Prostatic Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1838-7640
- Volume :
- 11
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Theranostics
- Publication Type :
- Academic Journal
- Accession number :
- 33754029
- Full Text :
- https://doi.org/10.7150/thno.55814