Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155.

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.
Mesh Terms:
Analysis of Variance, BRCA1 Protein, Blotting, Southern, Chromatin Immunoprecipitation, DNA Repair, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Histone Deacetylase 2, Humans, Immunohistochemistry, Immunoprecipitation, In Situ Hybridization, MicroRNAs, Microarray Analysis, Mutation, Missense, Reverse Transcriptase Polymerase Chain Reaction
Nat. Med.
Date: Oct. 01, 2011
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