Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155

Suhwan Chang, Rui Hong Wang, Keiko Akagi, Kyung Ae Kim, Betty K. Martin, Luca Cavallone, Diana C. Haines, Mark Basik, Phuong Mai, Elizabeth Poggi, Claudine Isaacs, Lai M. Looi, Kein S. Mun, Mark H. Greene, Stephen W. Byers, Soo H. Teo, Chu Xia Deng, Shyam K. Sharan

Research output: Contribution to journalArticlepeer-review

202 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1275-1282
Number of pages8
JournalNature medicine
Volume17
Issue number10
DOIs
StatePublished - Oct 2011
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

Fingerprint

Dive into the research topics of 'Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155'. Together they form a unique fingerprint.

Cite this