title: Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155.
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.
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
authors.forename: Suhwan
authors.initials: S
authors.lastname: Chang
authors.forename: Rui-Hong
authors.initials: RH
authors.lastname: Wang
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.forename: Kyung-Ae
authors.initials: KA
authors.lastname: Kim
authors.forename: Betty K
authors.initials: BK
authors.lastname: Martin
authors.forename: Luca
authors.initials: L
authors.lastname: Cavallone
authors.forename: Diana C
authors.initials: DC
authors.lastname: Haines
authors.forename: Mark
authors.initials: M
authors.lastname: Basik
authors.forename: Phuong
authors.initials: P
authors.lastname: Mai
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Poggi
authors.forename: Claudine
authors.initials: C
authors.lastname: Isaacs
authors.forename: Lai M
authors.initials: LM
authors.lastname: Looi
authors.forename: Kein S
authors.initials: KS
authors.lastname: Mun
authors.forename: Mark H
authors.initials: MH
authors.lastname: Greene
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Byers
authors.forename: Soo H
authors.initials: SH
authors.lastname: Teo
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: Shyam K
authors.initials: SK
authors.lastname: Sharan
mesh_terms: D000704:Analysis of Variance; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D015139:Blotting, Southern; D047369:Chromatin Immunoprecipitation; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics* / Q000502:physiology; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000378:metabolism*; D046228:Microarray Analysis; D020125:Mutation, Missense / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2