Article | Published:

Transcriptional regulation of BRCA1 expression by a metabolic switch

Nature Structural & Molecular Biology volume 17, pages 14061413 (2010) | Download Citation

Abstract

Though the linkages between germline mutations of BRCA1 and hereditary breast cancer are well known, recent evidence suggests that altered BRCA1 transcription may also contribute to sporadic forms of breast cancer. Here we show that BRCA1 expression is controlled by a dynamic equilibrium between transcriptional coactivators and co-repressors that govern histone acetylation and DNA accessibility at the BRCA1 promoter. Eviction of the transcriptional co-repressor and metabolic sensor, C terminal–binding protein (CtBP), has a central role in this regulation. Loss of CtBP from the BRCA1 promoter through estrogen induction, depletion by RNA interference or increased NAD+/NADH ratio leads to HDAC1 dismissal, elevated histone acetylation and increased BRCA1 transcription. The active control of chromatin marks, DNA accessibility and gene expression at the BRCA1 promoter by this 'metabolic switch' provides an important molecular link between caloric intake and tumor suppressor expression in mammary cells.

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Acknowledgements

This research was supported by the Intramural Research Program of the US National Institutes of Health, the US National Cancer Institute, the US National Institute on Aging and the Argentinean Agency of Science and Technology (ANPCyT, PICT 2006-00228). We thank P.M. Glazer (Yale University) for the gift of the BRCA1 promoter dual reporter.

Author information

Affiliations

  1. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, Maryland, USA.

    • Li-Jun Di
    • , Alfonso G Fernandez
    •  & Kevin Gardner
  2. Department of Biological Chemistry, School of Sciences, University of Buenos Aires, Buenos Aires, Argentina.

    • Adriana De Siervi
  3. Laboratory of Immunology, National Institute on Aging, Baltimore, Maryland, USA.

    • Dan L Longo

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Contributions

L.-J.D. and A.G.F. carried out the experiments. A.D. and D.L.L. helped write the paper and contributed valuable reagents. L.-J.D. and K.G. designed experiments and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kevin Gardner.

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DOI

https://doi.org/10.1038/nsmb.1941

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