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PMID: 23624935 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

BRCA1 is a negative modulator of the PRC2 complex.

The EMBO journal ·Vol. 32 ·No. 11 ·2013-05-29 ·Pages 1584-97

Wang L, Zeng X, Chen S, Ding L, Zhong J, Zhao JC, Wang L, Sarver A, Koller A, Zhi J, Ma Y, Yu J, Chen J, Huang H

Abstract

The Polycomb-repressive complex 2 (PRC2) is important for maintenance of stem cell pluripotency and suppression of cell differentiation by promoting histone H3 lysine 27 trimethylation (H3K27me3) and transcriptional repression of differentiation genes. Here we show that the tumour-suppressor protein BRCA1 interacts with the Polycomb protein EZH2 in mouse embryonic stem (ES) and human breast cancer cells. The BRCA1-binding region in EZH2 overlaps with the noncoding RNA (ncRNA)-binding domain, and BRCA1 expression inhibits the binding of EZH2 to the HOTAIR ncRNA. Decreased expression of BRCA1 causes genome-wide EZH2 re-targeting and elevates H3K27me3 levels at PRC2 target loci in both mouse ES and human breast cancer cells. BRCA1 deficiency blocks ES cell differentiation and enhances breast cancer migration and invasion in an EZH2-dependent manner. These results reveal that BRCA1 is a key negative modulator of PRC2 and that loss of BRCA1 inhibits ES cell differentiation and enhances an aggressive breast cancer phenotype by affecting PRC2 function.

MeSH Terms
Animals BRCA1 Protein/genetics,metabolism Cell Differentiation Cell Line, Tumor Cell Movement Embryonic Stem Cells/metabolism Enhancer of Zeste Homolog 2 Protein Female Gene Expression Regulation, Neoplastic Histones/metabolism Humans Lysine/metabolism Methylation Mice Polycomb Repressive Complex 2/genetics,metabolism Protein Binding RNA, Untranslated/metabolism
Chemicals
BRCA1 Protein BRCA1 protein, human Histones RNA, Untranslated EZH2 protein, human Enhancer of Zeste Homolog 2 Protein Ezh2 protein, mouse Polycomb Repressive Complex 2 Lysine
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Wang Lan
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Zeng Xianzhuo
Chen Shuai
Ding Liya
Zhong Jian
Zhao Jonathan C
Wang Liguo
Sarver Aaron
Koller Antonius
Zhi Jizu
Ma Yupo
Yu Jindan
Chen Junjie
Huang Haojie
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2013.95
Published
2013-05-29
Epub
2013-00-26
Pages
1584-97
Language
English
Region
England
NLM ID
8208664
PMCID
PMC3671259
Subset
IM
Grants
NCI NIH HHS · R00 CA129565 · United States
NCI NIH HHS · CA134514 · United States
NCI NIH HHS · K99/R00CA129565 · United States
NCI NIH HHS · CA130908 · United States
NCI NIH HHS · R01 CA130908 · United States
NCI NIH HHS · R01 CA134514 · United States
External Links
PubMed source DOI: 10.1038/emboj.2013.95 PMC Full Text View journal details
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