BRD4 and Cancer: going beyond transcriptional regulation

Abstract

BRD4, member of the Bromodomain and Extraterminal (BET) protein family, is largely acknowledged in cancer for its role in super-enhancers (SEs) organization and oncogenes expression regulation. Inhibition of BRD4 shortcuts the communication between SEs and target promoters with a subsequent cell-specific repression of oncogenes to which cancer cells are addicted and cell death. To date, this is the most credited mechanism of action of BET inhibitors, a class of small molecules targeting BET proteins which are currently in clinical trials in several cancer settings.However, recent evidence indicates that BRD4 relevance in cancer goes beyond its role in transcription regulation and identifies this protein as a keeper of genome stability.Indeed, a non-transcriptional role of BRD4 in controlling DNA damage checkpoint activation and repair as well as telomere maintenance has been proposed, throwing new lights into the multiple functions of this protein and opening new perspectives on the use of BETi in cancer. Here we discuss the current available information on non-canonical, non-transcriptional functions of BRD4 and on their implications in cancer biology. Integrating this information with the already known BRD4 role in gene expression regulation, we propose a "common" model to explain BRD4 genomic function. Furthermore, in light of the transversal function of BRD4, we provide new interpretation for the cytotoxic activity of BETi and we discuss new possibilities for a wide and focused employment of these drugs in clinical settings.

Keywords: BET inhibitors; BRD4; Cancer; DNA damage response; Telomere regulation; Transcriptional regulation; Unconventional function.

Fig. 1

a Schematic representation of BRD4 function in the organization and assembly of SE. Binding to hyperacetylated chromatin regions, BRD4 recruits the Mediator complex promoting the assembly of a large platform of transcription regulating proteins, that forms a bridge between SE and Promoter, favoring and stabilizing the binding of RNA-PolII. BRD4 also interacts and activates P-TEFb stimulating transition of RNA-PolII into active elongation. b Effect BETi on SE organization. BETi compete with acetylated residues for the binding at the BRD4 bromodomains releasing BRD4 from chromatin and disassembling the interaction between SE and promoter, reducing RNA-PolII throughput and blocking transcription of key oncogenes

Fig. 2

a Schematic representation of BRD4 function in DSB repair. H4Ac and γH2AX accumulate at DSBs triggering BRD4 recruitment. BRD4 facilitates and stabilizes the interaction of 53BP1 that in turn serves as adaptor for the assembly and activation of DNA repair machinery. b Effect of BETi on DNA repair system. BETi compete with acetylated residues for the binding at the BRD4 bromodomains releasing BRD4 from DSBs, destabilizing the DNA repair machinery and inducing accumulation of DNA alterations up to cell death. The function of BRD4 on DNA repair suggests a possible synergistic effect of BETi and DNA damaging agents (like radiation or platinum-based therapy) or specific inhibitors of DDR

Fig. 3

a Schematic representation of the possible BRD4 functions in telomere elongation. Increased histone acetylation and H2AX phosphorylation accumulate on telomeres, promoting BRD4 binding that in turn facilitates the assembly of telomere protection complex and promotes the activity of Telomerase. Since post-translational modification plays a fundamental role in telomere complexes regulation, it is likely that the kinase and/or the actetyltransferase function of BRD4 may take part to this process. For example, BRD4 may further promote acetylation of histone in the telomeric regions (red arrow) which in turn promotes telomere elongation. In addition, BRD4 may directly affect the acetylation (green arrow) or phosphorylation (blue arrow) of telomerase or other proteins of the telomere protection complex, promoting their activity. Indeed, TERT phosphorylation has been shown to be required for telomerase activation. b Effect of BETi on telomere regulation. BETi compete with acetylated histones for the binding at the BRD4 bromodomains releasing BRD4 from short telomere, destabilizing telomere protection complex organization and reducing Telomerase activity. The progressive shortening of telomere leads cancer cells to senescence or cell death. This structural effect in addition with the cancer specific effect of BRD4 on TERT promoter regulation may represent a possible strategy to target Telomerase function selectively in cancer cells or a strategy to improve telomerase inhibitors efficacy