Open AccessCDKN1C (p57KIP2) Is a Direct Target of EZH2 and Suppressed by Multiple Epigenetic Mechanisms in Breast Cancer Cells
Author(s) -
Xiaojing Yang,
R. Krishna Murthy Karuturi,
Feng Sun,
Meiyee Aau,
Kun Yu,
RongGuang Shao,
Lance D. Miller,
Patrick Tan,
Qiang Yu
Publication year - 2009
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0005011
Subject(s) - ezh2 , epigenetics , cancer research , histone , cancer epigenetics , histone methyltransferase , biology , histone deacetylase , breast cancer , dna methylation , histone h3 , cancer , genetics , gene expression , gene
CDKN1C (encoding tumor suppressor p57 KIP2 ) is a cyclin-dependent kinase (CDK) inhibitor whose family members are often transcriptionally downregulated in human cancer via promoter DNA methylation. In this study, we show that CDKN1C is repressed in breast cancer cells mainly through histone modifications. In particular, we show that CDKN1C is targeted by histone methyltransferase EZH2-mediated histone H3 lysine 27 trimethylation (H3K27me3), and can be strongly activated by inhibition of EZH2 in synergy with histone deacetylase inhibitor. Consistent with the overexpression of EZH2 in a variety of human cancers including breast cancer, CDKN1C in these cancers is downregulated, and breast tumors expressing low levels of CDKN1C are associated with a poor prognosis. We further show that assessing both EZH2 and CDKN1C expression levels as a measurement of EZH2 pathway activity provides a more predictive power of disease outcome than that achieved with EZH2 or CDKN1C alone. Taken together, our study reveals a novel epigenetic mechanism governing CDKN1C repression in breast cancer. Importantly, as a newly identified EZH2 target with prognostic value, it has implications in patient stratification for cancer therapeutic targeting EZH2-mediated gene repression.