Supercharging BRD4 with NUT in carcinoma

NUT carcinoma (NC) is an extremely aggressive squamous cancer with no effective therapy. NC is driven, most commonly, by the BRD4-NUT fusion oncoprotein. BRD4-NUT combines the chromatin-binding bromo- and extraterminal domain-containing (BET) protein, BRD4, with an unstructured, poorly understood protein, NUT, which recruits and activates the histone acetyltransferase (HAT) p300. Recruitment of p300 to chromatin by BRD4 is believed to lead to the formation of hyperacetylated nuclear foci, as seen by immunofluorescence. BRD4-NUT nuclear foci correspond with massive contiguous regions of chromatin co-enriched with BRD4-NUT, p300, and acetylated histones, termed ‘megadomains’ (MD). Megadomains stretch for as long as 2 MB. Proteomics has defined a BRD4-NUT chromatin complex in which members that associate with BRD4 also exist as rare NUT-fusion partners. This suggests that the common pathogenic denominator is the presence of both BRD4 and NUT, and that the function of BRD4-NUT may mimic that of wild-type BRD4. If so, then MDs may function as massive super-enhancers, activating transcription in a BET-dependent manner. Common targets of MDs across multiple NCs and tissues are three stem cell-related transcription factors frequently implicated in cancer: MYC, SOX2, and TP63. Recently, MDs were found to form a novel nuclear sub-compartment, called subcompartment M (subM), where MD-MD interactions occur both intra- and inter-chromosomally. Included in subM are MYC, SOX2, and TP63. Here we explore the possibility that if MDs are simply large super-enhancers, subM may exist in other cell systems, with broad implications for how 3D organization of the genome may function in gene regulation and maintenance of cell identity. Finally, we discuss how our knowledge of BRD4-NUT function has been leveraged for the therapeutic development of first-in-class BET inhibitors and other targeted strategies.