BET Family Protein BRD4: An Emerging Actor in NFκB Signaling in Inflammation and Cancer

Abstract

NFκB (Nuclear Factor-κ-light-chain-enhancer of activated B cells) signaling elicits global transcriptional changes by activating cognate promoters and through genome-wide remodeling of cognate regulatory elements called "super enhancers". BET (Bromodomain and Extra-Terminal domain) protein family inhibitor studies have implicated BET protein member BRD4 and possibly other BET proteins in NFκB-dependent promoter and super-enhancer modulation. Members of the BET protein family are known to bind acetylated chromatin to facilitate access by transcriptional regulators to chromatin, as well as to assist the activity of transcription elongation complexes via CDK9/pTEFb. BET family member BRD4 has been shown to bind non-histone proteins and modulate their activity. One such protein is RELA, the NFκB co-activator. Specifically, BRD4 binds acetylated RELA, which increases its transcriptional transactivation activity and stability in the nucleus. In aggregate, this establishes an intimate link between NFκB and BET signaling, at least via BRD4. The present review provides a brief overview of the structure and function of BET family proteins and then examines the connections between NFκB and BRD4 signaling, using the inflammatory response and cancer cell signaling as study models. We also discuss the potential of BET inhibitors for relief of aberrant NFκB signaling in cancer, focusing on non-histone, acetyl-lysine binding functions.

Keywords: BET inhibition; NFκB; acetylation B cell non-Hodgkin lymphoma; chromatin looping; transcription.

Figure 1

Schematic of domain organization of BET (bromodomain and extra-terminal domain) family proteins and the function of BRD4 in the regulation of promoter and enhancer activity. (A) Domain organization of human BET family members BRD4, BRD2, BRD3, and BRDT, as indicated. BET proteins contain two bromodomains (BD1 and BD2, respectively) and an extra-terminal domain (ET). BRD4 (long form) contains a carboxyterminal domain (CTD) that is not present in the other BET family members; (B) Schematic representation of the functions of BET family member BRD4 in the regulation of promoter and enhancer function (includes “super-enhancers”; see text for details). Through its BD1 and BD2 domains, BRD4 binds to acetylated lysines (Ac) in histones or transcription factors (TF). The binding of acetylated histones by BRD4, at transcription start sites (TSS), mediates transcriptional co-activation and elongation via RNA polymerase II (RNA pol II) and Mediator (Med) and pTEFb signaling complexes, respectively (see text for details). BRD4 can also bind acetylated lysines in histones or TF in enhancer elements, thereby contributing to long-range control of gene activity (see text for details). TF binding sites are depicted as horizontal rectangles.

Figure 2

Schematic model for the binding of BRD4 to acetylated lysine-310 of RELA/p65 and the role of this interaction in the transcriptional activation of NFκB. Stimulus-dependent acetylation of RELA at lysine-310 by p300 induces the recruitment of BRD4 to the promoter via its bromodomains. BRD4 further activates CDK9 to phosphorylate the CTD (C-terminal domain) of RNA polymerase II and to facilitate the RNA pol II-mediated transcription of NFκB target genes. The p50 factor is a processed form of the REL family member p105 (NFκB1) that heterodimerizes with RELA/p65 and that is required for its transcriptional activation functions.