Oncogenesis by sequestration of CBP/p300 in transcriptionally inactive hyperacetylated chromatin domains.
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.
Reynoird
Nicolas
N
INSERM, U823, Université Joseph Fourier-Grenoble 1, Institut Albert Bonniot, Grenoble, France.
Schwartz
Brian E
BE
Delvecchio
Manuela
M
Sadoul
Karin
K
Meyers
David
D
Mukherjee
Chandrani
C
Caron
Cécile
C
Kimura
Hiroshi
H
Rousseaux
Sophie
S
Cole
Philip A
PA
Panne
Daniel
D
French
Christopher A
CA
Khochbin
Saadi
S
D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
D018797:Cell Cycle Proteins; D002843:Chromatin; D050881:E1A-Associated p300 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C000630260:NUTM1 protein, human; C494360:EP300 protein, human