دورية أكاديمية
BRD4 inhibitor GNE987 exerts anti-cancer effects by targeting super-enhancers in neuroblastoma
| العنوان: | BRD4 inhibitor GNE987 exerts anti-cancer effects by targeting super-enhancers in neuroblastoma |
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| المؤلفون: | Yan-Ling Chen, Xiao-Lu Li, Gen Li, Yan-Fang Tao, Ran Zhuo, Hai-Bo Cao, Wan-yan Jiao, Zhi-Heng Li, Zhen-Hong Zhu, Fang Fang, Yi Xie, Xin-Mei Liao, Di Wu, Hai-Rong Wang, Juan-Juan Yu, Si-Qi Jia, Yang Yang, Chen-Xi Feng, Peng-Cheng Yang, Xiao-Dong Fei, Jian-Wei Wang, Yun-Yun Xu, Guang-Hui Qian, Zi-Mu Zhang, Jian Pan |
| المصدر: | Cell & Bioscience, Vol 12, Iss 1, Pp 1-20 (2022) |
| بيانات النشر: | BMC, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Biotechnology LCC:Biology (General) LCC:Biochemistry |
| مصطلحات موضوعية: | BRD4, Neuroblastoma, Broad H3K27ac domain, Super-enhancer, PROTAC, Biotechnology, TP248.13-248.65, Biology (General), QH301-705.5, Biochemistry, QD415-436 |
| الوصف: | Abstract Background Neuroblastoma (NB) is a common extracranial malignancy with high mortality in children. Recently, super-enhancers (SEs) have been reported to play a critical role in the tumorigenesis and development of NB via regulating a wide range of oncogenes Thus, the synthesis and identification of chemical inhibitors specifically targeting SEs are of great urgency for the clinical therapy of NB. This study aimed to characterize the activity of the SEs inhibitor GNE987, which targets BRD4, in NB. Results In this study, we found that nanomolar concentrations of GNE987 markedly diminished NB cell proliferation and survival via degrading BRD4. Meanwhile, GNE987 significantly induced NB cell apoptosis and cell cycle arrest. Consistent with in vitro results, GNE987 administration (0.25 mg/kg) markedly decreased the tumor size in the xenograft model, with less toxicity, and induced similar BRD4 protein degradation to that observed in vitro. Mechanically, GNE987 led to significant downregulation of hallmark genes associated with MYC and the global disruption of the SEs landscape in NB cells. Moreover, a novel candidate oncogenic transcript, FAM163A, was identified through analysis of the RNA-seq and ChIP-seq data. FAM163A is abnormally transcribed by SEs, playing an important role in NB occurrence and development. Conclusion GNE987 destroyed the abnormal transcriptional regulation of oncogenes in NB by downregulating BRD4, which could be a potential therapeutic candidate for NB. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2045-3701 |
| Relation: | https://doaj.org/toc/2045-3701 |
| DOI: | 10.1186/s13578-022-00769-8 |
| URL الوصول: | https://doaj.org/article/dc438f9673894ec1ae734a44d291ecc9 |
| رقم الأكسشن: | edsdoj.438f9673894ec1ae734a44d291ecc9 |
| قاعدة البيانات: | Directory of Open Access Journals |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 20453701 |
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| DOI: | 10.1186/s13578-022-00769-8 |