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

Oncogene volume 33, pages 1736–1742 (2014)Cite this article

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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.

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Acknowledgements

This work was supported by the Samuel Waxman Cancer Research Foundation (CAF and JEB), the US National Institutes of Health grant 1R01CA124633 (CAF), the Adolescent and Young Adult Gap Fund (CAF and JEB), and the American Association for Cancer Research grant 10-20-03-FREN. We would like to thank Dr Nicholas Haining for assistance with GSEA. Many thanks to Dr Paola Dal Cin for providing fluorescent in situ hybridization probes, and to Mr Dan Shea for his assistance with fluorescent in situ hybridization photomicrographs. High-throughput siRNA assays were performed at the Institute of Chemistry and Cell Biology, Longwood Campus (ICCB-L, http://iccb.med.harvard.edu/).

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  1. A R Grayson and E M Walsh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Brigham and Women’s Hospital, MA, Boston, USA

    A R Grayson, E M Walsh, M J Cameron, T Ashworth, J M Ambrose, A B Aserlind, H Wang, M J Kluk, J C Aster & C A French

  2. Harvard Medical School, MA, Boston, USA

    A R Grayson, E M Walsh, M J Cameron, T Ashworth, J M Ambrose, A B Aserlind, H Wang, M J Kluk, J E Bradner, J C Aster & C A French

  3. Department of Microbiology and Immunobiology, Harvard Medical School, MA, Boston, USA

    J Godec

  4. Department of Pediatric Oncology, Dana-Farber Cancer Institute, MA, Boston, USA

    J Godec

  5. Department of Biochemistry, University of Cambridge, Cambridge, UK

    G I Evan

  6. Department of Adult Oncology, Dana-Farber Cancer Institute, MA, Boston, USA

    J E Bradner

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Grayson, A., Walsh, E., Cameron, M. et al. MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. Oncogene 33, 1736–1742 (2014). https://doi.org/10.1038/onc.2013.126

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