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Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155

  1. Author:
    Chang, S. H.
    Wang, R. H.
    Akagi, K.
    Kim, K. A.
    Martin, B. K.
    Cavallone, L.
    Haines, D. C.
    Basik, M.
    Mai, P.
    Poggi, E.
    Isaacs, C.
    Looi, L. M.
    Mun, K. S.
    Greene, M. H.
    Byers, S. W.
    Teo, S. H.
    Deng, C. X.
    Sharan, S. K.
    Kathleen Cuningham Fdn, C.

  2. Author Address

    [Sharan, SK; Kathleen Cuningham Fdn Consortium] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Chang, SH; Kim, KA] NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Wang, RH; Deng, CX] NIDDK, Genet Dev & Dis Branch, Bethesda, MD USA. [Akagi, K] Ohio State Univ, Human Canc Genet Program, Dept Mol Virol, Columbus, OH 43210 USA. [Akagi, K] Ohio State Univ, Human Canc Genet Program, Dept Immunol, Columbus, OH 43210 USA. [Akagi, K] Ohio State Univ, Human Canc Genet Program, Dept Med Genet, Columbus, OH 43210 USA. [Martin, BK] NCI, Sci Applicat Int Corp SAIC Frederick, Frederick, MD 21701 USA. [Cavallone, L; Basik, M] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Cavallone, L] McGill Univ, Dept Oncol, Program Canc Genet, Montreal, PQ, Canada. [Cavallone, L] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada. [Haines, DC] NCI, Pathol Histotechnol Lab, SAIC Frederick, Frederick, MD 21701 USA. [Mai, P; Greene, MH] NCI, Clin Genet Branch, Rockville, MD USA. [Poggi, E; Isaacs, C; Byers, SW] Georgetown Univ, Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. [Looi, LM; Mun, KS] Univ Malaya, Dept Pathol, Med Ctr, Kuala Lumpur, Malaysia. [Teo, SH] Univ Malaya, Med Ctr, Dept Surg, Univ Malaya Canc Res Inst, Kuala Lumpur, Malaysia. [Teo, SH] Sime Darby Med Ctr, Canc Res Initiat Fdn, Kuala Lumpur, Malaysia.;Sharan, SK (reprint author), Peter MacCallum Canc Ctr, Melbourne, Vic, Australia;sharans@mail.nih.gov
    1. Year: 2011
    2. Date: Oct
  2. Journal: Nature Medicine
    1. 17
    2. 10
    3. Pages: 1275-U308
  4. Type of Article: Article
  5. ISSN: 1078-8956
  1. 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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External Sources

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  2. DOI: 10.1038/nm.2459
  3. View record in Web of Science®
  4. WOS: 000296022100046

Library Notes

  1. Fiscal Year: FY2011-2012
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