NUT midline carcinoma (NMC) belongs to a class of highly lethal and poorly 
differentiated epithelial cancers arising mainly in human midline organs. NMC is 
caused by the chromosome translocation-mediated fusion of the NUT (nuclear 
protein in testis) gene on chromosome 15 to a few other genes, most frequently 
the BRD4 gene on chromosome 19. The mechanism by which the BRD4-NUT fusion 
product blocks NMC cellular differentiation and contributes to oncogenesis 
remains elusive. In this study, we show that BRD4-NUT and BRD4 colocalize in 
discrete nuclear foci that are hyperacetylated but transcriptionally inactive. 
BRD4-NUT recruits histone acetyltransferases to induce histone hyperacetylation 
in these chromatin foci, which provide docking sites for accumulation of 
additional BRD4 and associated P-TEFB (positive transcription elongation factor 
b) complexes in the transcriptionally inactive BRD4-NUT foci. These molecular 
events lead to repression of a BRD4·P-TEFB downstream target gene c-fos, a 
component of activator protein 1 (AP-1), that directly regulates epithelial 
differentiation. Knockdown of BRD4-NUT in NMC cells disperses the 
transcriptionally inactive chromatin foci and releases the transcriptional 
activators to stimulate c-fos expression, leading to restoration of cellular 
differentiation. Our study provides a novel mechanism by which the BRD4-NUT 
oncogene perturbs BRD4 functions to block cellular differentiation and to 
contribute to the oncogenic progression in the highly aggressive NMC.