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

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.

An inhibitor of BRD4, GNE987, inhibits the growth of glioblastoma cells by targeting C-Myc and S100A16

“…C-Myc is a well-studied proto-oncogene; it acts as a master regulator of cell proliferation, and its upregulation has been demonstrated in GBM [11]. In this study, we also found that GNE987 interfered with C-Myc protein level in GBM cells, indicating that in GBM, GNE987 can exert an antitumor effect by inhibiting the Myc pathway, similar results also appear in neuroblastoma [7].…”

“…growth and increases apoptosis in neuroblastoma [7] and AML [8]. However, its anti-tumor activity and underlying mechanism in GBM are unavailable to date.…”

“…GNE987 is a PROTAC linked by von Hippel-Lindau (VHL) and BRD4 ligands. GNE987 reduces cell growth and increases apoptosis in neuroblastoma [ 7 ] and AML [ 8 ]. However, its anti-tumor activity and underlying mechanism in GBM are unavailable to date.…”

“…C-Myc is a well-studied oncogene whose upregulation has been demonstrated in various cancers, including gastric [ 9 ], breast [ 10 ], and GBM [ 11 ]. A recent study demonstrated that GNE987 rapidly and persistently degrades BRD4 and inhibits downstream targets such as C-Myc in neuroblastoma [ 7 ]. BRD4 belongs to the BET family, which recognizes acetylated lysine residues on histone and non-histone chromatin factors to manage gene expression [ 12 , 13 ].…”

Histone methylation modification patterns and relevant M-RiskScore in acute myeloid leukemia

“…ADAMTS15 is used to predict the survival of human breast carcinoma with the inhibitory functions to tumor growth and invasion of colorectal cancers ( Porter et al., 2006 ; Viloria et al., 2009 ). The high FAM163A expression is associated with short survival time in hepatocellular carcinoma and affects the occurrence and development of neuroblastoma ( Chen et al., 2022 ; Qiao et al., 2019 ). The methylation status of CDO1 was specifically high in small bowel cancer (SBC) ( Kojima et al., 2019 ), which indicates it is a biomarker of SBC.…”