دورية أكاديمية
Predicting novel therapies and targets: regulation of notch3 by the Bromodomain protein BRD4
| العنوان: | Predicting novel therapies and targets: regulation of notch3 by the Bromodomain protein BRD4 |
|---|---|
| المؤلفون: | Villar-Prados, Alejandro, Wu, Sherry Y., Court, Karem A., Ma, Shaolin, LaFargue, Christopher, Chowdhury, Mamur A., Engelhardt, Margaret I., Ivan, Cristina, Ram, Prahlad T., Wang, Ying, Baggerly, Keith, Rodriguez-Aguayo, Cristian, Lopez-Berestein, Gabriel, Ming-Yang, Shyh, Maloney, David J., Yoshioka, Makoto, Strovel, Jeffrey W., Roszik, Jason, Sood, Anil K. |
| بيانات النشر: | American Association for Cancer Research |
| سنة النشر: | 2019 |
| المجموعة: | The University of Queensland: UQ eSpace |
| مصطلحات موضوعية: | Potential Therapeutic Target, Ovarian-Cancer, Gene-Expression, Bet, Inhibition, Resistance, Pathway, Chromatin, Enhancer, Cells, 1306 Cancer Research, 2730 Oncology |
| الوصف: | Systematic approaches for accurate repurposing of targeted therapies are needed. We developed and aimed to biologically validate our therapy predicting tool (TPT) for the repurposing of targeted therapies for specific tumor types by testing the role of Bromodomain and Extra-Terminal motif inhibitors (BETi) in inhibiting BRD4 function and downregulating Notch3 signaling in ovarian cancer.Utilizing established ovarian cancer preclinical models, we carried out in vitro and in vivo studies with clinically relevant BETis to determine their therapeutic effect and impact on Notch3 signaling.Treatment with BETis or siRNA-mediated BRD4 knockdown resulted in decreased cell viability, reduced cell proliferation, and increased cell apoptosis in vitro. In vivo studies with orthotopic mouse models demonstrated that treatment with BETi decreased tumor growth. In addition, knockdown of BRD4 with doxycycline-inducible shRNA increased survival up to 50% (P < 0.001). Treatment with either BETis or BRD4 siRNA decreased Notch3 expression both in vitro and in vivo BRD4 inhibition also decreased the expression of NOTCH3 targets, including HES1 Chromatin immunoprecipitation revealed that BRD4 was present at the NOTCH3 promoter.Our findings provide biological validation for the TPT by demonstrating that BETis can be an effective therapeutic agent for ovarian cancer by downregulating Notch3 expression.The TPT could rapidly identify candidate drugs for ovarian or other cancers along with novel companion biomarkers. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1538-8514 1535-7163 |
| العلاقة: | orcid:0000-0002-6051-4252; P30 CA016672; UH3TR000943; P50 CA217685; U01 CA213759 P50 CA098258; R35 CA209904; U54CA096300/U54CA096297; Not set; P30CA16672; RP101502; RP140106; RP170067; P50CA098258; P30CA016672; U54CA096297 |
| الإتاحة: | https://doi.org/10.1158/1535-7163.MCT-18-0365Test https://espace.library.uq.edu.au/view/UQ:d0da1e1Test |
| رقم الانضمام: | edsbas.2C2503D6 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 15388514 15357163 |
|---|