In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 5_Supplement ( 2013-05-01), p. B39-B39
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 displaced by acetyl histone mimetic BET inhibitor, JQ1, which prevents binding of BET bromodomains to acetylated histones. BRD4-NUT is also required to maintain MYC expression in NMC cell lines, as shown by a dramatic decrease in MYC expression upon JQ1 treatment and knockdown of BRD4-NUT with NUT specific siRNAs. 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. Citation Format: Erica M. Walsh, Adlai R. Grayson, Michael J. Cameron, Jernej Godec, Todd Ashworth, Alexandra B. Aserlind, Hongfang Wang, Gerard Evan, Michael J. Kluk, James E. Bradner, Jon C. Aster, Christopher A. French. MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B39.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.PMS-B39
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2062135-8
SSG:
12
Permalink