The mechanisms behind the therapeutic activity of BET bromodomain inhibition

Abstract

The bromodomain and extraterminal (BET) protein Brd4 recruits transcriptional regulatory complexes to acetylated chromatin. While Brd4 is considered to be a general transcriptional regulator, pharmacological inhibition of BET proteins shows therapeutic activity in a variety of different pathologies, particularly in models of cancer and inflammation. Such effects have been attributed to a specific set of downstream target genes whose expression is disproportionately sensitive to pharmacological targeting of BET proteins. Emerging evidence links the transcriptional consequences of BET inhibition to the association of Brd4 with enhancer elements, which tend to be involved in lineage-specific gene regulation. Furthermore, Brd4 engages in direct regulatory interactions with several DNA-binding transcription factors to influence their disease-relevant functions. Here we review the current understanding of molecular mechanisms that underlie the promising therapeutic effects of BET bromodomain inhibition.

Figure 1. Domain architecture of human Brd4 and other BET proteins

Three isoforms of Brd4 are indicated. ET: extra-terminal domain. CTD: C-terminal domain. Isoform B of Brd4 has a unique C-terminus, which interacts with condensin II complexes (Floyd et al., 2013). Brdt and Brd2 have multiple isoforms, which are not indicated here. In some studies, the CTD of Brd4 and Brdt is referred to as a C-terminal motif (CTM).

Figure 2. Protein-protein interactions involving Brd4

Depicted are some of the critical protein-protein interactions employed by Brd4 that could be relevant to the therapeutic effects of BET inhibitors. Mediator, Jmjd6, and P-TEFb are candidate effectors recruited by Brd4 to regulate transcription by Pol II. Acetylated histones and/or TFs have been suggested as potential recruiters of Brd4 to promoters and/or enhancer regions.

Figure 3. Lineage-specific arrangements of Brd4-occupied enhancers at the MYC locus that correlate with sensitivity to pharmacological BET inhibition

Brd4 occupancy is represented by red triangles as measured by ChIP-seq in either MM1.S cells (top) (Loven et al., 2013) or in MLL-AF9/Nras^G12D acute myeloid leukemia (Shi et al., 2013). In these two cell lines, MYC transcription is highly sensitive to BET inhibition.