Theranostics, 2021-01, Vol.11 (10), p.4809-4824
2021
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- WD repeat domain 5 promotes chemoresistance and Programmed Death-Ligand 1 expression in prostate cancer
- Ist Teil von
- Theranostics, 2021-01, Vol.11 (10), p.4809-4824
- Ort / Verlag
- Australia: Ivyspring International Publisher Pty Ltd
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. 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, and . The mechanism of WDR5 was explored by RNA-sequencing and chromatin immunoprecipitation (ChIP). 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 and . 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. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1838-7640eISSN: 1838-7640DOI: 10.7150/thno.55814Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7978315
- Format
- –
- Schlagworte
- Aged, Animals, Antineoplastic Agents - therapeutic use, Apoptosis, Apoptosis - drug effects, Apoptosis - genetics, Aurora Kinase A - genetics, Aurora Kinase A - metabolism, B7-H1 Antigen - genetics, B7-H1 Antigen - metabolism, Biphenyl Compounds - pharmacology, Cancer therapies, Cell cycle, Cell Cycle Proteins - genetics, Cell Cycle Proteins - metabolism, Cell Line, Tumor, Cell Proliferation - drug effects, Cell Proliferation - genetics, Chemotherapy, Cisplatin - therapeutic use, Cyclin B1 - genetics, Cyclin B1 - metabolism, Dihydropyridines - pharmacology, DNA damage, DNA methylation, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Drug Resistance, Neoplasm - genetics, E2F1 Transcription Factor - genetics, E2F1 Transcription Factor - metabolism, Epigenetics, Flow cytometry, Gene expression, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Intracellular Signaling Peptides and Proteins - genetics, Male, Medical prognosis, Mice, Mice, Nude, Middle Aged, Neoplasm Transplantation, PC-3 Cells, Phase transitions, Polo-Like Kinase 1, Prostate cancer, Prostatic Neoplasms - drug therapy, Prostatic Neoplasms - genetics, Prostatic Neoplasms - metabolism, Protein Serine-Threonine Kinases - genetics, Protein Serine-Threonine Kinases - metabolism, Proto-Oncogene Proteins - genetics, Proto-Oncogene Proteins - metabolism, Research Paper, RNA, Small Interfering, Roles, Standard deviation, Survivin - genetics, Survivin - metabolism, Tumor Escape - drug effects, Tumor Escape - genetics