Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155

An Erratum to this article was published on 07 November 2011

This article has been updated

Abstract

BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates but the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: R1699Q mutant ES cells show reduced survival and differentiation defects.
Figure 2: Identification of miR-155 upregulation in R1699Q mutant cells and its effect on ES cell differentiation.
Figure 3: BRCA1 negatively controls miR-155 expression.
Figure 4: Mechanism of miR-155 repression by BRCA1.
Figure 5: Physiological relevance of miR-155 upregulation in BRCA1-deficient tumors.

Change history

  • 07 November 2011

     In the version of this article initially published, Shyam K Sharan's affiliation was erroneously listed as affiliation 7, when it should have been affiliation 1. The error has been corrected for the PDF and HTML versions of this article.

References

  1. O'Donovan, P.J. & Livingston, D.M. BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. Carcinogenesis 31, 961–967 (2010).

    Article  CAS  Google Scholar 

  2. Venkitaraman, A.R. Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu. Rev. Pathol. 4, 461–487 (2009).

    Article  CAS  Google Scholar 

  3. 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 

  4. Xia, Y., Pao, G.M., Chen, H.W., Verma, I.M. & Hunter, T. Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein. J. Biol. Chem. 278, 5255–5263 (2003).

    Article  CAS  Google Scholar 

  5. Baer, R. & Ludwig, T. The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity. Curr. Opin. Genet. Dev. 12, 86–91 (2002).

    Article  CAS  Google Scholar 

  6. Bork, P. et al. A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins. FASEB J. 11, 68–76 (1997).

    Article  CAS  Google Scholar 

  7. Abbott, D.W. et al. BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription-coupled DNA repair. J. Biol. Chem. 274, 18808–18812 (1999).

    Article  CAS  Google Scholar 

  8. Li, S. et al. Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage. J. Biol. Chem. 274, 11334–11338 (1999).

    Article  CAS  Google Scholar 

  9. Cantor, S.B. et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105, 149–160 (2001).

    Article  CAS  Google Scholar 

  10. Yu, X., Chini, C.C., He, M., Mer, G. & Chen, J. The BRCT domain is a phospho-protein binding domain. Science 302, 639–642 (2003).

    Article  CAS  Google Scholar 

  11. Cortez, D., Wang, Y., Qin, J. & Elledge, S.J. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286, 1162–1166 (1999).

    Article  CAS  Google Scholar 

  12. Ruffner, H., Jiang, W., Craig, A.G., Hunter, T. & Verma, I.M. BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site. Mol. Cell Biol. 19, 4843–4854 (1999).

    Article  CAS  Google Scholar 

  13. Chen, J. Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage. Cancer Res. 60, 5037–5039 (2000).

    CAS  PubMed  Google Scholar 

  14. Ouchi, M. et al. BRCA1 phosphorylation by Aurora-A in the regulation of G2 to M transition. J. Biol. Chem. 279, 19643–19648 (2004).

    Article  CAS  Google Scholar 

  15. Szabo, C.I. & King, M.C. Inherited breast and ovarian cancer. Hum. Mol. Genet. 4 Spec No, 1811–1817 (1995).

    Article  CAS  Google Scholar 

  16. Williams, R.S., Lee, M.S., Hau, D.D. & Glover, J.N. Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1. Nat. Struct. Mol. Biol. 11, 519–525 (2004).

    Article  CAS  Google Scholar 

  17. Clapperton, J.A. et al. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nat. Struct. Mol. Biol. 11, 512–518 (2004).

    Article  CAS  Google Scholar 

  18. Lovelock, P.K. et al. Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants? Breast Cancer Res. 9, R82 (2007).

    Article  Google Scholar 

  19. Gómez García, E.B. et al. A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history. Breast Cancer Res. 11, R8 (2009).

    Article  Google Scholar 

  20. Chang, S., Biswas, K., Martin, B.K., Stauffer, S. & Sharan, S.K. Expression of human BRCA1 variants in mouse ES cells allows functional analysis of BRCA1 mutations. J. Clin. Invest. 119, 3160–3171 (2009).

    Article  CAS  Google Scholar 

  21. Tam, W., Hughes, S.H., Hayward, W.S. & Besmer, P. Avian bic, a gene isolated from a common retroviral site in avian leukosis virus-induced lymphomas that encodes a noncoding RNA, cooperates with c-myc in lymphomagenesis and erythroleukemogenesis. J. Virol. 76, 4275–4286 (2002).

    Article  CAS  Google Scholar 

  22. van den Berg, A. et al. High expression of B-cell receptor inducible gene BIC in all subtypes of Hodgkin lymphoma. Genes Chromosom. Cancer 37, 20–28 (2003).

    Article  CAS  Google Scholar 

  23. Metzler, M., Wilda, M., Busch, K., Viehmann, S. & Borkhardt, A. High expression of precursor microRNA-155/BIC RNA in children with Burkitt lymphoma. Genes Chromosom. Cancer 39, 167–169 (2004).

    Article  CAS  Google Scholar 

  24. Kluiver, J. et al. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J. Pathol. 207, 243–249 (2005).

    Article  CAS  Google Scholar 

  25. O'Connell, R.M. et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J. Exp. Med. 205, 585–594 (2008).

    Article  CAS  Google Scholar 

  26. Costinean, S. et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc. Natl. Acad. Sci. USA 103, 7024–7029 (2006).

    Article  CAS  Google Scholar 

  27. Yamamoto, M. et al. miR-155, a Modulator of FOXO3a protein expression, is underexpressed and cannot be upregulated by stimulation of HOZOT, a line of multifunctional Treg. PLoS ONE 6, e16841 (2011).

    Article  CAS  Google Scholar 

  28. Kong, W. et al. MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer. J. Biol. Chem. 285, 17869–17879 (2010).

    Article  CAS  Google Scholar 

  29. Gironella, M. et al. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc. Natl. Acad. Sci. USA 104, 16170–16175 (2007).

    Article  CAS  Google Scholar 

  30. Jiang, S. et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res. 70, 3119–3127 (2010).

    Article  CAS  Google Scholar 

  31. Kanellopoulou, C. et al. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev. 19, 489–501 (2005).

    Article  CAS  Google Scholar 

  32. Deffenbaugh, A.M., Frank, T.S., Hoffman, M., Cannon-Albright, L. & Neuhausen, S.L. Characterization of common BRCA1 and BRCA2 variants. Genet. Test. 6, 119–121 (2002).

    Article  CAS  Google Scholar 

  33. Iorio, M.V. et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 65, 7065–7070 (2005).

    CAS  PubMed  Google Scholar 

  34. Volinia, S. et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl. Acad. Sci. USA 103, 2257–2261 (2006).

    Article  CAS  Google Scholar 

  35. Brodie, S.G. et al. Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice. Oncogene 20, 7514–7523 (2001).

    Article  CAS  Google Scholar 

  36. Liu, X. et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc. Natl. Acad. Sci. USA 104, 12111–12116 (2007).

    Article  CAS  Google Scholar 

  37. Bartel, D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    Article  CAS  Google Scholar 

  38. Cable, P.L. et al. Novel consensus DNA-binding sequence for BRCA1 protein complexes. Mol. Carcinog. 38, 85–96 (2003).

    Article  CAS  Google Scholar 

  39. Aiyar, S.E., Cho, H., Lee, J. & Li, R. Concerted transcriptional regulation by BRCA1 and COBRA1 in breast cancer cells. Int. J. Biol. Sci. 3, 486–492 (2007).

    Article  CAS  Google Scholar 

  40. 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 

  41. Wang, Q., Zhang, H., Kajino, K. & Greene, M.I. BRCA1 binds c-Myc and inhibits its transcriptional and transforming activity in cells. Oncogene 17, 1939–1948 (1998).

    Article  CAS  Google Scholar 

  42. Yarden, R.I. & Brody, L.C. BRCA1 interacts with components of the histone deacetylase complex. Proc. Natl. Acad. Sci. USA 96, 4983–4988 (1999).

    Article  CAS  Google Scholar 

  43. Wang, R.H. et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol. Cell 32, 11–20 (2008).

    Article  Google Scholar 

  44. Lee, M.S. et al. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res. 70, 4880–4890 (2010).

    Article  CAS  Google Scholar 

  45. Rowling, P.J., Cook, R. & Itzhaki, L.S. Toward classification of BRCA1 missense variants using a biophysical approach. J. Biol. Chem. 285, 20080–20087 (2010).

    Article  CAS  Google Scholar 

  46. Shang, Y., Hu, X., DiRenzo, J., Lazar, M.A. & Brown, M. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103, 843–852 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Acharya, K. Biswas, R. Chittela, I. Daar, K. Reilly and A. Spurdle for helpful discussions and critical review of the manuscript. We also thank D.M. Livingston (Dana-Farber Cancer Institute) and D.L. Turner (University of Michigan) for providing DNA constructs; D. Swing for help with BAC transgenic mice and allograft experiment; W.D. Foulkes, A. Spurdle, H. Thorne, Y.C. Har, P.S. Yee, A. Saleh, the Georgetown-Lombardi Comprehensive Cancer Center, Familial Cancer and Histopathology and Tissue Share Resources, who helped with the human tumor samples; S. Burkett for cytogenetic analysis; C.H. Kim for microarray analysis, and A. Kane and R. Frederickson for illustrations. The research was sponsored by the Center for Cancer Research, US National Cancer Institute and US National Institutes of Health.

Author information

Authors and Affiliations

Authors

Consortia

Contributions

S.C. conceived the idea, conducted all the experiments and wrote the manuscript, R.-H.W. and C.-X.D. helped with xenograft experiment, provided mouse tumor samples and cell lines, K.A. carried out bioinformatics analysis, K.-A.K. helped with experiments, B.K.M. helped with mouse work, D.C.H. performed histopathological analysis, L.C. analyzed human tumor samples, M.B., P.M., M.H.G., KConFab, L.M.L., K.S.M., S.H.T., E.P., C.I. and S.W.B. provided human tumor samples, S.K.S. conceived the idea, supervised the study and wrote the manuscript.

Corresponding author

Correspondence to Shyam K Sharan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10, Supplementary Tables 1–6, Supplementary Methods and Supplementary Discussion (PDF 2307 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chang, S., Wang, RH., Akagi, K. et al. Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155. Nat Med 17, 1275–1282 (2011). https://doi.org/10.1038/nm.2459

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2459

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing