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Transcriptional regulation of BRCA1 expression by a metabolic switch

Nature Structural & Molecular Biology volume 17, pages 1406–1413 (2010)Cite this article

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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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Figure 1: Estrogen induction increases histone acetylation at the BRCA1 promoter.
Figure 2: A multicomponent co-repressor complex containing CtBP is dismissed and elongation factors are recruited to the BRCA1 promoter after estrogen induction.
Figure 3: CtBP regulates BRCA1 expression by influencing histone acetylation at the BRCA1 promoter.
Figure 4: CtBP control of BRCA1 is gene specific, functionally influences cell cycle progression and is chromatin dependent.
Figure 5: TSA mimics estrogen-induced activation of BRCA1 by increasing p300-dependent histone acetylation at the BRCA1 promoter.
Figure 6: CtBP functions as a metabolic switch to control BRCA1 expression.
Figure 7: Hypoxia inhibits estrogen-induced changes in the NAD+/NADH ratio and selectively represses estrogen induction of BRCA1 transcription.

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References

  1. Landis, S.H., Murray, T., Bolden, S. & Wingo, P.A. Cancer statistics, 1999. CA Cancer J. Clin. 49, 8–31 (1999).

    Article  CAS  Google Scholar 

  2. Ford, D. et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am. J. Hum. Genet. 62, 676–689 (1998).

    Article  CAS  Google Scholar 

  3. Turner, N.C. et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26, 2126–2132 (2007).

    Article  CAS  Google Scholar 

  4. Catteau, A. & Morris, J.R. BRCA1 methylation: a significant role in tumour development? Semin. Cancer Biol. 12, 359–371 (2002).

    Article  CAS  Google Scholar 

  5. Wilson, C.A. et al. Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat. Genet. 21, 236–240 (1999).

    Article  CAS  Google Scholar 

  6. Xu, C.F., Chambers, J.A. & Solomon, E. Complex regulation of the BRCA1 gene. J. Biol. Chem. 272, 20994–20997 (1997).

    Article  CAS  Google Scholar 

  7. Rice, J.C., Massey-Brown, K.S. & Futscher, B.W. Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. Oncogene 17, 1807–1812 (1998).

    Article  CAS  Google Scholar 

  8. Mueller, C.R. & Roskelley, C.D. Regulation of BRCA1 expression and its relationship to sporadic breast cancer. Breast Cancer Res. 5, 45–52 (2003).

    Article  CAS  Google Scholar 

  9. Bindra, R.S. et al. Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Res. 65, 11597–11604 (2005).

    Article  CAS  Google Scholar 

  10. De Siervi, A. et al. Transcriptional autoregulation by BRCA1. Cancer Res. 70, 532–542 (2010).

    Article  CAS  Google Scholar 

  11. Deng, C.X. BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Res. 34, 1416–1426 (2006).

    Article  CAS  Google Scholar 

  12. Mullan, P.B., Quinn, J.E. & Harkin, D.P. The role of BRCA1 in transcriptional regulation and cell cycle control. Oncogene 25, 5854–5863 (2006).

    Article  CAS  Google Scholar 

  13. Spillman, M.A. & Bowcock, A.M. BRCA1 and BRCA2 mRNA levels are coordinately elevated in human breast cancer cells in response to estrogen. Oncogene 13, 1639–1645 (1996).

    CAS  PubMed  Google Scholar 

  14. Marks, J.R. et al. BRCA1 expression is not directly responsive to estrogen. Oncogene 14, 115–121 (1997).

    Article  CAS  Google Scholar 

  15. Lane, T.F. et al. Expression of Brca1 is associated with terminal differentiation of ectodermally and mesodermally derived tissues in mice. Genes Dev. 9, 2712–2722 (1995).

    Article  CAS  Google Scholar 

  16. Gorski, J.J., Kennedy, R.D., Hosey, A.M. & Harkin, D.P. The complex relationship between BRCA1 and ERα in hereditary breast cancer. Clin. Cancer Res. 15, 1514–1518 (2009).

    Article  CAS  Google Scholar 

  17. Chinnadurai, G. The transcriptional corepressor CtBP: a foe of multiple tumor suppressors. Cancer Res. 69, 731–734 (2009).

    Article  CAS  Google Scholar 

  18. Turner, N., Tutt, A. & Ashworth, A. Hallmarks of 'BRCAness' in sporadic cancers. Nat. Rev. Cancer 4, 814–819 (2004).

    Article  CAS  Google Scholar 

  19. Gorski, J.J. et al. BRCA1 transcriptionally regulates genes associated with the basal-like phenotype in breast cancer. Breast Cancer Res. Treat. 122, 721–731 (2010).

    Article  CAS  Google Scholar 

  20. Fjeld, C.C., Birdsong, W.T. & Goodman, R.H. Differential binding of NAD+ and NADH allows the transcriptional corepressor carboxyl-terminal binding protein to serve as a metabolic sensor. Proc. Natl. Acad. Sci. USA 100, 9202–9207 (2003).

    Article  CAS  Google Scholar 

  21. Zhang, Q., Piston, D.W. & Goodman, R.H. Regulation of corepressor function by nuclear NADH. Science 295, 1895–1897 (2002).

    CAS  PubMed  Google Scholar 

  22. Kim, T.H. et al. A high-resolution map of active promoters in the human genome. Nature 436, 876–880 (2005).

    Article  CAS  Google Scholar 

  23. Ferreira, R., Magnaghi-Jaulin, L., Robin, P., Harel-Bellan, A. & Trouche, D. The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase. Proc. Natl. Acad. Sci. USA 95, 10493–10498 (1998).

    Article  CAS  Google Scholar 

  24. Cunliffe, V.T. Eloquent silence: developmental functions of Class I histone deacetylases. Curr. Opin. Genet. Dev. 18, 404–410 (2008).

    Article  CAS  Google Scholar 

  25. Wang, A., Schneider-Broussard, R., Kumar, A.P., MacLeod, M.C. & Johnson, D.G. Regulation of BRCA1 expression by the Rb-E2F pathway. J. Biol. Chem. 275, 4532–4536 (2000).

    Article  CAS  Google Scholar 

  26. Zhang, Q., Yao, H., Vo, N. & Goodman, R.H. Acetylation of adenovirus E1A regulates binding of the transcriptional corepressor CtBP. Proc. Natl. Acad. Sci. USA 97, 14323–14328 (2000).

    Article  CAS  Google Scholar 

  27. Yu, X., Wu, L.C., Bowcock, A.M., Aronheim, A. & Baer, R. The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J. Biol. Chem. 273, 25388–25392 (1998).

    Article  CAS  Google Scholar 

  28. Aprelikova, O.N. et al. BRCA1-associated growth arrest is RB-dependent. Proc. Natl. Acad. Sci. USA 96, 11866–11871 (1999).

    Article  CAS  Google Scholar 

  29. Fan, S. et al. Disruption of BRCA1 LXCXE motif alters BRCA1 functional activity and regulation of RB family but not RB protein binding. Oncogene 20, 4827–4841 (2001).

    Article  CAS  Google Scholar 

  30. Saunders, A., Core, L.J. & Lis, J.T. Breaking barriers to transcription elongation. Nat. Rev. Mol. Cell Biol. 7, 557–567 (2006).

    Article  CAS  Google Scholar 

  31. Aiyar, S.E. et al. Attenuation of estrogen receptor α-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor. Genes Dev. 18, 2134–2146 (2004).

    Article  CAS  Google Scholar 

  32. Rahl, P.B. et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010).

    Article  CAS  Google Scholar 

  33. Stossi, F., Madak-Erdogan, Z. & Katzenellenbogen, B.S. Estrogen receptor α represses transcription of early target genes via p300 and CtBP1. Mol. Cell. Biol. 29, 1749–1759 (2009).

    Article  CAS  Google Scholar 

  34. Xu, C.F. et al. Distinct transcription start sites generate two forms of BRCA1 mRNA. Hum. Mol. Genet. 4, 2259–2264 (1995).

    Article  CAS  Google Scholar 

  35. Lin, J.M. et al. Transcription factor binding and modified histones in human bidirectional promoters. Genome Res. 17, 818–827 (2007).

    Article  CAS  Google Scholar 

  36. Brooks, R.F. Continuous protein synthesis is required to maintain the probability of entry into S phase. Cell 12, 311–317 (1977).

    Article  CAS  Google Scholar 

  37. Rodríguez-Enriquez, S. et al. Control of cellular proliferation by modulation of oxidative phosphorylation in human and rodent fast-growing tumor cells. Toxicol. Appl. Pharmacol. 215, 208–217 (2006).

    Article  Google Scholar 

  38. Meng, A.X. et al. Hypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells. Radiother. Oncol. 76, 168–176 (2005).

    Article  CAS  Google Scholar 

  39. Schones, D.E. et al. Dynamic regulation of nucleosome positioning in the human genome. Cell 132, 887–898 (2008).

    Article  CAS  Google Scholar 

  40. Andres, J.L. et al. Regulation of BRCA1 and BRCA2 expression in human breast cancer cells by DNA-damaging agents. Oncogene 16, 2229–2241 (1998).

    Article  CAS  Google Scholar 

  41. Stöckl, P., Hutter, E., Zwerschke, W. & Jansen-Durr, P. Sustained inhibition of oxidative phosphorylation impairs cell proliferation and induces premature senescence in human fibroblasts. Exp. Gerontol. 41, 674–682 (2006).

    Article  Google Scholar 

  42. Zong, W.X., Ditsworth, D., Bauer, D.E., Wang, Z.Q. & Thompson, C.B. Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev. 18, 1272–1282 (2004).

    Article  CAS  Google Scholar 

  43. Zhang, Q., Yoshimatsu, Y., Hildebrand, J., Frisch, S.M. & Goodman, R.H. Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. Cell 115, 177–186 (2003).

    Article  CAS  Google Scholar 

  44. Semenza, G.L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634 (2010).

    Article  CAS  Google Scholar 

  45. Trinklein, N.D. et al. An abundance of bidirectional promoters in the human genome. Genome Res. 14, 62–66 (2004).

    Article  CAS  Google Scholar 

  46. Ramirez-Carrozzi, V.R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009).

    Article  CAS  Google Scholar 

  47. Byun, J.S. et al. Dynamic bookmarking of primary response genes by p300 and RNA polymerase II complexes. Proc. Natl. Acad. Sci. USA 106, 19286–19291 (2009).

    Article  CAS  Google Scholar 

  48. Jang, M.K. et al. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell 19, 523–534 (2005).

    Article  CAS  Google Scholar 

  49. Zippo, A. et al. Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation. Cell 138, 1122–1136 (2009).

    Article  CAS  Google Scholar 

  50. Tan-Wong, S.M., French, J.D., Proudfoot, N.J. & Brown, M.A. Dynamic interactions between the promoter and terminator regions of the mammalian BRCA1 gene. Proc. Natl. Acad. Sci. USA 105, 5160–5165 (2008).

    Article  CAS  Google Scholar 

  51. Driggers, P.H. & Segars, J.H. Estrogen action and cytoplasmic signaling pathways. Part II: the role of growth factors and phosphorylation in estrogen signaling. Trends Endocrinol. Metab. 13, 422–427 (2002).

    Article  CAS  Google Scholar 

  52. Fullwood, M.J. et al. An oestrogen-receptor-α-bound human chromatin interactome. Nature 462, 58–64 (2009).

    Article  CAS  Google Scholar 

  53. Jeffy, B.D. et al. An estrogen receptor-α/p300 complex activates the BRCA-1 promoter at an AP-1 site that binds Jun/Fos transcription factors: repressive effects of p53 on BRCA-1 transcription. Neoplasia 7, 873–882 (2005).

    Article  CAS  Google Scholar 

  54. Hockings, J.K., Degner, S.C., Morgan, S.S., Kemp, M.Q. & Romagnolo, D.F. Involvement of a specificity proteins-binding element in regulation of basal and estrogen-induced transcription activity of the BRCA1 gene. Breast Cancer Res. 10, R29 (2008).

    Article  Google Scholar 

  55. Fan, S. et al. p300 Modulates the BRCA1 inhibition of estrogen receptor activity. Cancer Res. 62, 141–151 (2002).

    CAS  PubMed  Google Scholar 

  56. Blackshear, P.E. et al. Brca1 and Brca2 expression patterns in mitotic and meiotic cells of mice. Oncogene 16, 61–68 (1998).

    Article  CAS  Google Scholar 

  57. Thiery, J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002).

    Article  CAS  Google Scholar 

  58. Cleary, M.P. & Grossmann, M.E. Obesity and breast cancer: the estrogen connection. Endocrinology 150, 2537–2542 (2009).

    Article  CAS  Google Scholar 

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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.

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Authors and 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.

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Correspondence to Kevin Gardner.

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Di, LJ., Fernandez, A., De Siervi, A. et al. Transcriptional regulation of BRCA1 expression by a metabolic switch. Nat Struct Mol Biol 17, 1406–1413 (2010). https://doi.org/10.1038/nsmb.1941

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