Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155 |
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Authors: | Chang Suhwan Wang Rui-Hong Akagi Keiko Kim Kyung-Ae Martin Betty K Cavallone Luca;Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer Haines Diana C Basik Mark Mai Phuong Poggi Elizabeth Isaacs Claudine Looi Lai M Mun Kein S Greene Mark H Byers Stephen W Teo Soo H Deng Chu-Xia Sharan Shyam K |
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Institution: | Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA. |
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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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