BRCA1 is a negative modulator of the PRC2 complex

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 tumoursuppressor 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.

HOTAIR: An Oncogenic Long Non-Coding RNA in Human Cancer

“…These observations suggest that HOTAIR regulates gene expression in the transregulatory fashion [5]. In addition, the effect of HOTAIR on EZH2 can be competed binding by BRCA1, a critical player in DNA damage response and genomic integrity [6]. HOTAIR is also shown to interact with the lysine-specific histone demethylase 1A (LSD1).…”

Noncoding RNAs in breast cancer

“…HOTAIR is an RNA scaffold, and the 5 0 and 3 0 domains of HOTAIR are involved in recruiting two critical epigenetic protein complexes, Polycomb Repressive Complex 2 (PRC2) and the LSD1-CoREST-REST H3K4 demethylase complex, to regulate gene expression [177]. In addition, Wang et al [178] recently found that BRCA1 can compete with HOTAIR to bind EZH2, a component of PRC2, to attenuate PRC2 activity. Therefore, loss of BRCA1 or upregulation of HOTAIR results in the reprogramming of the genome-wide PRC2-binding pattern in breast epithelial cells, leading to the altered methylation signature found in aggressive breast cancer cells [178].…”

“…In addition, Wang et al [178] recently found that BRCA1 can compete with HOTAIR to bind EZH2, a component of PRC2, to attenuate PRC2 activity. Therefore, loss of BRCA1 or upregulation of HOTAIR results in the reprogramming of the genome-wide PRC2-binding pattern in breast epithelial cells, leading to the altered methylation signature found in aggressive breast cancer cells [178]. Recently HOTAIR has been shown to be upregulated in tamoxifen-resistant breast cancer tissues compared with their primary counterparts [179].…”

Roles of enhancer of zeste homolog 2: From skeletal muscle differentiation to rhabdomyosarcoma carcinogenesis

“…Therefore, decreased levels of BRCA1 preclude ESC differentiation and enhance EZH2-dependent breast cancer cell migration and invasion. 89 Several long ncRNAs interact with EZH2, and their tissue-specific expression confirms the crucial role of PRC2 in organogenesis.…”