MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma

Abstract

NUT midline carcinoma (NMC) is an aggressive type of squamous cell carcinoma that is defined by the presence of BRD-NUT fusion oncogenes, which encode chimeric proteins that block differentiation and maintain tumor growth. BRD-NUT oncoproteins contain two bromodomains whose binding to acetylated histones is required for the blockade of differentiation in NMC, but the mechanisms by which BRD-NUT act remain uncertain. Here we provide evidence that MYC is a key downstream target of BRD4-NUT. Expression profiling of NMCs show that the set of genes whose expression is maintained by BRD4-NUT is highly enriched for MYC upregulated genes, and MYC and BRD4-NUT protein expression is strongly correlated in primary NMCs. More directly, we find that BRD4-NUT associates with the MYC promoter and is required to maintain MYC expression in NMC cell lines. Moreover, both siRNA knockdown of MYC and a dominant-negative form of MYC, omomyc, induce differentiation of NMC cells. Conversely, differentiation of NMC cells induced by knockdown of BRD4-NUT is abrogated by enforced expression of MYC. Together, these findings suggest that MYC is a downstream target of BRD4-NUT that is required for maintenance of NMC cells in an undifferentiated, proliferative state. Our findings support a model in which dysregulation of MYC by BRD-NUT fusion proteins has a central role in the pathogenesis of NMC.

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

“…Both MXD1 and MXD4 are members of the MAD gene family and regulate MYC , leading to cell growth in differentiating tissues 50. Grayson et al have identified that MYC is a key transcriptional target of BRD4–NUTM1 fusion and that dysregulation of MYC by BRD4–NUTM1 fusion has a central role in the pathogenesis of in NUT midline carcinoma 51. Our data revealed an increase in both NUTM1 mRNA and protein expression in tumor tissue.…”

The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains

“…BRD4-NUT nuclear foci correspond to chromatin-bound 'megadomains' that drive ectopic transcription in naïve cells BRD4-NUT associates with chromatin via the dual bromodomains of BRD4 (Dey et al 2003;French et al 2008;Grayson et al 2014), forming ∼80-100 large foci that can be visualized in interphase nuclei and metaphase chromosomes (Fig. 1A).…”

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

“…Approximately 80% of NMCs harbor a chromosomal translocation that fuses NUT to BRD3 or BRD4, which encode bromodomain and extraterminal domain (BET) proteins that regulate gene expression in part through the sequestration of p300 histone acetyltransferase activity and other transcriptional machinery to specific genomic loci (5). MYC is a major target of BET proteins, and NMC cells harboring BRD4-NUT fusions are dependent on MYC for maintenance of an undifferentiated, proliferative state (6,7). Amplification or overexpression of the MYC oncogene is also associated with poor prognosis in other solid tumor types, such as medulloblastoma (8,9), breast cancer (10), ovarian cancer (11), prostate cancer (12), and lung cancer (13).…”