BRD4: An emerging prospective therapeutic target in glioma

Abstract

Despite advances in treatment, the prognosis for glioma patients remains poor. Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) protein family, plays an important role in controlling oncogene expression and genome stability. In recent years, numerous BRD4 inhibitors have entered clinical trials and achieved exciting results in tumor treatment. Recent clinical studies have shown that BRD4 expression in glioma is significantly higher than in the adjacent normal brain tissue. BRD4 inhibitors effectively penetrate the blood-brain barrier and target glioma tumor tissues but have little effect on normal brain tissues. Thus, BRD4 is a target for the treatment of glioma. In this study, we discuss the progress in the use of BRD4 inhibitors for glioma treatment, their mechanism of action, and their broad potential clinical application.

Keywords: BRD4; bromodomain and extraterminal protein family; glioma; small molecular inhibitors.

Graphical abstract

Figure 1

Interactions with BRD4 domains BD1 and BD2 bind to acetylated histone and non-histone proteins, an extra-terminal (ET) domain interacts with several chromatin regulators, and a C-terminal motif (CTM) interacts with pTEFb to facilitate transcription factors.

Figure 2

Drug selectivity of BRD4 small-molecule inhibitors

Figure 3

Schematic diagram showing the BRD4 inhibitor therapy for GBM (A–C) The mechanisms of BRD4 inhibitors in the treatment of GBM (A), glioma stem cells (B), and H3K27M mutated glioma cells and EGFRvIII mutated glioma cells (C). HOTAIR, lncRNA HOX transcript antisense RNA; GBM, glioblastoma.

Figure 4

Schematic diagram showing the combination therapy including BRD4 inhibitor for GBM (A–C) The mechanisms of combination therapy including BRD4 inhibitor in the treatment of GBM (A), glioma stem cells (B), and H3K27M mutated glioma cells and EGFRvIII mutated glioma cells (C). EGFR TKI, epidermal growth factor receptor tyrosine kinase inhibitor; EGFRvIII, epidermal growth factor receptor variant III; TMZ, temozolomide.