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Oncogene. 2014 Mar 27;33(13):1736-42. doi: 10.1038/onc.2013.126. Epub 2013 Apr 22.

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

Author information

1
1] Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
2
1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Department of Biochemistry, University of Cambridge, Cambridge, UK.
4
1] Harvard Medical School, Boston, MA, USA [2] Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

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 shows 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.

PMID:
23604113
PMCID:
PMC3942361
DOI:
10.1038/onc.2013.126
[Indexed for MEDLINE]
Free PMC Article
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