期刊
EMBO JOURNAL
卷 29, 期 17, 页码 2943-2952出版社
WILEY
DOI: 10.1038/emboj.2010.176
关键词
Brdt; cancer testis factor; feed forward; H3K56; oncogene
资金
- INCa-DHOS
- ANR
- ARC
- Dana Farber/Harvard Cancer Center [5P30CA06516-44]
- US National Institutes of Health [1R01CA124633]
- National Cancer Institute's Initiative for Chemical Genetics [N01-CO-12400]
- NIGMS [GM62437]
- FAMRI
- Rhone-Alpes region
- Fondation pour la Recherche Medicale
- Grants-in-Aid for Scientific Research [21570196] Funding Source: KAKEN
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. The EMBO Journal (2010) 29, 2943-2952. doi: 10.1038/emboj.2010.176; Published online 30 July 2010
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