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Cell Rep. 2014 Oct 9;9(1):248-260. doi: 10.1016/j.celrep.2014.08.069. Epub 2014 Oct 2.

Transformation resistance in a premature aging disorder identifies a tumor-protective function of BRD4.

Author information

1
National Cancer Institute, NIH, Bethesda, MD 20892, USA.
2
National Cancer Institute, NIH, Bethesda, MD 20892, USA; Cancer Epigenetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London WC2A 3PX, UK; UCL Cancer Institute, University College London, London WC1E 6DD, UK.
3
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert-Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
4
National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
5
National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: mistelit@mail.nih.gov.

Abstract

Advanced age and DNA damage accumulation are prominent risk factors for cancer. The premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS) provides a unique opportunity for studying the interplay between DNA damage and aging-associated tumor mechanisms, given that HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neoplastic transformation. Resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells, leading to inhibition of oncogenic dedifferentiation. BRD4 also inhibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals. BRD4-mediated tumor protection is clinically relevant given that a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific roles for BRD4 in tumorigenesis.

PMID:
25284786
PMCID:
PMC4194066
DOI:
10.1016/j.celrep.2014.08.069
[Indexed for MEDLINE]
Free PMC Article

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