Bromodomain-containing protein 4 (BRD4) and BRD4-NUT fusion protein (BRD4 / BRD4-NUT)

Bromodomain-containing protein 4 (BRD4) is a member of the Bromodomain and Extra-Terminal (BET) family of epigenetic readers that plays a critical role in regulating gene expression by binding to acetylated lysine residues on histone tails (UniProt P57682). It recruits transcriptional machinery, such as the positive transcription elongation factor b (P-TEFb), to promoters and enhancers to facilitate RNA polymerase II-mediated transcription (PubMed: 24385483). In NUT midline carcinoma (NMC), a rare and aggressive squamous cell cancer, a chromosomal translocation typically fuses the BRD4 gene to the NUTM1 (NUT) gene, creating the BRD4-NUT fusion protein (NCBI Gene ID: 23476). This fusion protein drives oncogenesis by creating large megadomains of hyperacetylated chromatin that lead to the aberrant overexpression of growth-promoting genes like MYC (PubMed: 29033130). Therapeutic strategies primarily involve small-molecule BET inhibitors that competitively bind to the bromodomains of BRD4 and BRD4-NUT, thereby displacing them from chromatin and suppressing oncogenic signaling (PubChem CID: 46907787). While BET inhibitors have shown promise in clinical trials, challenges such as dose-limiting toxicities like thrombocytopenia and the development of drug resistance remain significant hurdles (PubMed: 28468912).

Other names

BRD4-NUTM1 (UniProt P57682)HUNK1 (UniProt P57682)MCAP (UniProt P57682)Bromodomain-containing protein 4 (UniProt P57682)NUT midline carcinoma protein (PubMed: 29033130)

BET inhibitors competitively bind to the acetyl-lysine binding pockets of the bromodomains (BD1 and BD2) of BRD4 and the BRD4-NUT fusion protein. This action prevents the proteins from associating with acetylated histones on chromatin, thereby disrupting the recruitment of transcriptional co-activators and suppressing the expression of downstream oncogenic targets such as MYC and BCL2 (PubMed: 24385483, 29033130).