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BRD4 inhibitor GNE987 exerts anti-cancer effects by targeting super-enhancers in neuroblastoma

Authors :
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
Source :
Cell & Bioscience. 12
Publication Year :
2022
Publisher :
Springer Science and Business Media LLC, 2022.

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.

Details

ISSN :
20453701
Volume :
12
Database :
OpenAIRE
Journal :
Cell & Bioscience
Accession number :
edsair.doi.dedup.....e8c995ac2defff35e75afd3e7490baf6