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Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155

Nature Medicine volume 17, pages 1275–1282 (2011)Cite this article

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An Erratum to this article was published on 07 November 2011

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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.

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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.

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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.

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Authors and Affiliations

  1. Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA

    Suhwan Chang, Kyung-Ae Kim & Shyam K Sharan

  2. Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA

    Rui-Hong Wang & Chu-Xia Deng

  3. Departments of Molecular Virology, Human Cancer Genetics Program, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio, USA

    Keiko Akagi

  4. Science Applications International Corporation (SAIC-Frederick, National Cancer Institute at Frederick, Frederick, Maryland, USA

    Betty K Martin

  5. Lady Davis Institute, Jewish General Hospital, Montréal, Quebec, Canada

    Luca Cavallone & Mark Basik

  6. Departments of Oncology and Human Genetics, Program in Cancer Genetics, McGill University, Montréal, Quebec, Canada

    Luca Cavallone

  7. Pathology Histotechnology Laboratory, SAIC-Frederick, National Cancer Institute at Frederick, Frederick, Maryland, USA

    Diana C Haines

  8. Clinical Genetics Branch, National Cancer Institute, Rockville, Maryland, USA

    Phuong Mai & Mark H Greene

  9. Georgetown-Lombardi Comprehensive Cancer Center Georgetown University, Washington, DC, USA

    Elizabeth Poggi, Claudine Isaacs & Stephen W Byers

  10. Department of Pathology, University Malaya Medical Center, Kuala Lumpur, Malaysia

    Lai M Looi & Kein S Mun

  11. Department of Surgery University Malaya Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia

    Soo H Teo

  12. Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Kuala Lumpur, Malaysia

    Soo H Teo

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Consortia

Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab)

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.

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Correspondence to Shyam K Sharan.

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The authors declare no competing financial interests.

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

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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

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