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

Nicolas Reynoird1, Brian E Schwartz, Manuela Delvecchio

  • 1INSERM, U823, Université Joseph Fourier-Grenoble 1, Institut Albert Bonniot, Grenoble, France.

The EMBO Journal
|August 3, 2010
PubMed

Insights

A chromosomal translocation creates a BRD4-NUT fusion protein that drives aggressive cancers by hijacking p300, leading to p53 inactivation. Restoring p300 function triggers cancer cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • A specific chromosomal translocation, t(15;19), generates the BRD4-NUT fusion oncogene in aggressive carcinomas.
  • The fusion protein involves BRD4, a double bromodomain protein, and NUT (nuclear protein in testis), a testis-specific protein.

Purpose of the Study:

  • To elucidate the oncogenic mechanism of the BRD4-NUT fusion protein.
  • To investigate the role of p300 and p53 in BRD4-NUT-driven tumorigenesis.

Main Methods:

  • Utilized a patient-derived cell line harboring the BRD4-NUT fusion.
  • Performed knockdown experiments to assess the functional impact of BRD4-NUT.
  • Investigated protein-protein interactions and chromatin modifications.

Main Results:

  • BRD4-NUT recruits and hyperactivates p300, leading to transcriptionally inactive chromatin domains.
  • p300 sequestration by BRD4-NUT causes p53 inactivation, a key oncogenic event.
  • BRD4-NUT knockdown restored p300 and p53 activity, inducing cell differentiation and apoptosis.

Conclusions:

  • The aberrant activity of the testis-specific NUT protein in the BRD4-NUT fusion drives malignant transformation.
  • Targeting BRD4-NUT or restoring p300/p53 function presents potential therapeutic strategies for NUT-midline carcinomas.

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