Emerging roles of and therapeutic strategies targeting BRD4 in cancer

Abstract

The Bromodomain and Extra-terminal (BET) family of proteins were first recognized as important epigenetic regulators in inflammatory processes; however, there is increasing evidence to support the notion that BET proteins also play a critical role in ‘reading’ chromatin and recruiting chromatin-regulating enzymes to control gene expression in a number of pathologic processes, including cancer. To this end, the mechanisms by which BET proteins regulate chromatin remodeling and promote tumor-associated inflammation have been heavily studied over the past decade. This article to review the biology of BET protein dysfunction in promoting tumor-associated inflammation and cancer progression and the application of small molecule inhibitors that target specific BET proteins, alone or in combination with immunomodulatory agents as a novel therapeutic strategy for cancer patients.

PCNA Unloading Is Negatively Regulated by BET Proteins

“…During double-strand break repair, BRD4 interacts with 53BP1 and stabilizes it at the break sites (Li et al, 2018). BRD4 is regarded as a major therapeutic target in many diseases because of its pivotal roles in cell proliferation (Korb et al, 2017;Sun et al, 2018;White et al, 2019). Given that PCNA is important for nascent chromatin assembly, PCNA unloading from nascent DNA should be coordinated with nucleosome deposition.…”

Circ_0007841 promotes the progression of multiple myeloma via miR-338-3p/BRD4 axis

“…Bromodomain containing 4 (BRD4) is a crucial epigenetic protein, and it has been reported to elevate the levels of oncogenic proteins and accelerate the progression of cancers [20]. Zheng et al claimed that H19 accelerated the development of MM through up-regulating BRD4 via sponging miR-152-3p [21].…”

Nitroxoline: repurposing its antimicrobial to antitumor application

“…BRD4 is a member of the bromodomain and extraterminal (BET) family of proteins, (Jung et al, 2015) that contains two conserved tandem bromodomain motifs (BD1 and BD2) (White et al, 2019;Fu et al, 2015;Jung et al, 2015). It is expressed ubiquitously and is required for maintenance of chromatin stability.…”

“…It controls progression of the cell cycle. In cancer, BRD4 is dysregulated and contributes to changes in the chromatin remod-eling and gene transcription that mediate tumorogenesis (White et al, 2019;Jung et al, 2015). By phosphorylation it stimulates RNA polymerase II and regulates the transcription of various oncogenes that include c-Myc, cyclin dependent kinase 6 (CDK6), one of the essential oncogenes in various types of cancer, and Bcl-2 (Jung et al, 2015).…”