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NF-YA underlies EZH2 upregulation and is essential for proliferation of human epithelial ovarian cancer cells.
MedLine Citation:
PMID:  23360797     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Epithelial ovarian cancer (EOC) accounts for the most gynecological malignancy-associated deaths in the United States. Enhancer of zeste homolog 2 (EZH2), which silences gene expression through generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3), is often overexpressed in EOC and has been suggested as a therapeutic target. However, the mechanism underlying EZH2 overexpression in EOC is unknown. Here we show that EZH2 is upregulated at the transcription level, and two CCAAT boxes in the proximal regions of the human EZH2 gene promoter are critical for its transcription in EOC cells. Indeed, NF-YA, the regulatory subunit of the CCAAT binding transcription factor NF-Y, is expressed at higher levels in human EOCs compared with primary human ovarian surface epithelial (HOSE) cells. In addition, there is a positive correlation between expression of NF-YA and EZH2 in EOCs. Notably, high NF-YA expression predicts shorter overall survival in EOC patients. The association of NF-YA with the promoter of the human EZH2 gene is enhanced in human EOC cells compared with primary HOSE cells. Significantly, knockdown of NF-YA downregulates EZH2, decreases H3K27Me3 levels, and suppresses the growth of human EOC cells both in vitro and in a xenograft mouse model. Notably, NF-YA knockdown induces apoptosis of EOC cells and ectopic EZH2 expression partially rescues apoptosis induced by NF-YA knockdown. Together, these data reveal that NF-Y is a key regulator of EZH2 expression and is required for EOC cell proliferation, thus representing a novel target for developing EOC therapeutics.
Authors:
Azat Garipov; Hua Li; Benjamin G Bitler; Roshan J Thapa; Siddharth Balachandran; Rugang Zhang
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-29
Journal Detail:
Title:  Molecular cancer research : MCR     Volume:  -     ISSN:  1557-3125     ISO Abbreviation:  Mol. Cancer Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101150042     Medline TA:  Mol Cancer Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1Kazan Federal University.
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