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 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.

Automated summary

NUT carcinoma is an extremely aggressive squamous cancer driven by the BRD4-NUT fusion oncoprotein, offering potential therapeutic targets such as BET inhibitors. The BRD4-NUT complex recruits and activates histone acetyltransferase p300, forming hyperacetylated chromatin foci known as megadomains that regulate stem cell-related transcription factors. These megadomains also create a novel nuclear sub-compartment, called subcompartment M, with implications for 3D genome organization and gene regulation. Leveraging knowledge of BRD4-NUT function has led to the development of targeted therapies.