Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155

Publisher Website
Google Scholar
Abstract
BRCA1 loss of function is considered to promote tumorigenesis through impairment of the protein's role in DNA damage repair. By studying BRCA1 mutations that do not affect this function but still confer cancer predisposition, this report identifies a new function of BRCA1, the repression of miR-155 through modulation of HDAC activity. miR-155 increase correlates with BRCA1 loss or mutation in humans, and it likely to mediate some of the oncogenic effects of BRCA1 deficiency. 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.