Article

Oncogenesis by sequestration of CBP/p300 in transcriptionally inactive hyperacetylated chromatin domains.

INSERM, U823, Université Joseph Fourier-Grenoble 1, Institut Albert Bonniot, Grenoble, France.
The EMBO Journal (Impact Factor: 10.75). 09/2010; 29(17):2943-52. DOI: 10.1038/emboj.2010.176
Source: PubMed

ABSTRACT In a subset of poorly differentiated and highly aggressive carcinoma, a chromosomal translocation, t(15;19)(q13;p13), results in an in-frame fusion of the double bromodomain protein, BRD4, with a testis-specific protein of unknown function, NUT (nuclear protein in testis). In this study, we show that, after binding to acetylated chromatin through BRD4 bromodomains, the NUT moiety of the fusion protein strongly interacts with and recruits p300, stimulates its catalytic activity, initiating cycles of BRD4-NUT/p300 recruitment and creating transcriptionally inactive hyperacetylated chromatin domains. Using a patient-derived cell line, we show that p300 sequestration into the BRD4-NUT foci is the principal oncogenic mechanism leading to p53 inactivation. Knockdown of BRD4-NUT released p300 and restored p53-dependent regulatory mechanisms leading to cell differentiation and apoptosis. This study demonstrates how the off-context activity of a testis-specific factor could markedly alter vital cellular functions and significantly contribute to malignant cell transformation.

0 Followers
 · 
217 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rare childhood cancers have not benefited to the same extent from the gains that have been made for their frequently occurring counterparts. In recent years, this gap has been recognized and a number of vehicles now exist to improve outcome, including rare tumor groups, disease-specific registries, and clinics. The multitude of approaches has allowed significant progress, however, this framework is limited by patient number and is not inclusive for every type of rare childhood cancer. These shortcomings can be overcome by a single global unified approach to the study of rare childhood tumors. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
    Cancer Medicine 02/2015; DOI:10.1002/cam4.426
  • [Show abstract] [Hide abstract]
    ABSTRACT: NUT midline carcinoma (NMC) is a rare but highly aggressive cancer typically caused by the translocation t(15;19), which results in the formation of BRD4-NUT fusion oncoprotein. Previous studies have demonstrated that fusion of NUT protein with the double bromodomains of BRD4 may significantly alter cellular gene expression profile to contribute to NMC tumorigenesis. However, the mechanistic details of this BRD4-NUT function remains poorly understood. In this study, we examined the NUT function in transcriptional regulation by targeting it to a LacO transgene array integrated in U2OS 2-6-3 cells, which allow us to visualize how NUT alters in situ gene transcription dynamic. Using this system, we demonstrated that NUT protein tethered to the LacO locus recruits p300/CBP, induces histone hyperacetylation, and enriches BRD4 to the transgene array chromatin foci. We also discovered that, in BRD4-NUT expressed in NMC cells, the NUT moiety of the fusion protein anchored to chromatin by the double bromodomains also stimulates histone hyperacetylation, which causes BRD4 to bind tighter to chromatin. Consequently, multiple BRD4-interacting factors are recruited to the NUT-associated chromatin locus to activate in situ transgene expression. This gene transcription function was repressed by either expression of a dominant negative inhibitor of the p300-NUT interaction or treatment with (+)-JQ1, which dissociates BRD4 from the LacO chromatin locus. Our data supports a model in which BRD4-NUT-stimulated histone hyperacetylation recruits additional BRD4 and interacting partners to support transcriptional activation, which underlies the BRD4-NUT oncogenic mechanism in NMC. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 12/2014; DOI:10.1074/jbc.M114.600759 · 4.60 Impact Factor
  • Source
    ACS Chemical Biology 12/2014; 9(12). DOI:10.1021/cb5009469 · 5.36 Impact Factor

Full-text (2 Sources)

Download
42 Downloads
Available from
May 28, 2014