Yang, X. et al. CDKN1C (p57KPI2) is a direct target of EZH2 and suppressed by multiple epigenetic mechanisms in breast cancer cells. PLoS ONE 4, e5011

Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(4):e5011. DOI: 10.1371/journal.pone.0005011
Source: PubMed


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.

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    • "In addition to these proteins, multiple EZH2 target genes have been shown to be involved in EZH2-mediated cancer aggressiveness. These target genes include stathmin and Wnt antagonists in HCC [122,123]; bone morphogenetic protein receptor 1B in GBM [85]; p57 in breast and ovarian cancers [124,125]; DAB2IP, SLIT2, TIMP2/3, and CCN3/NOV in prostate cancer [126-129]; FOXC1, HOXC10, and RAD51 in breast cancer [130-132]; CXXC4 in gastric cancer [133]; MyoD in rhabdomyosarcoma [134]; rap1GAP in HN cancer [25]; CASZ1 in neuroblastoma [135]; and RUNX3 and KLF2 in multiple cancer types [136,137]. In addition, several molecules such as Bim, TRAIL, and FBXO32 play a role in apoptosis induced by the inhibition of EZH2 [138-140]. "
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    • "The cyclin-dependent kinase (CDK) inhibitor, CDKN1C (p57KIP2) encodes the tumor suppressor p57KIP2 protein. Reduced CDKN1C expression in various breast cancer cell lines was associated with EZH2 overexpression and increased H3K27me3 30. Upon treatment with the histone methylation inhibitor 3-deazaneplanocin A (DZNep), recovery of CDKN1C expression was observed suggesting a direct link between H3K27me3 and transcriptional suppression. "
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    ABSTRACT: Histone modifications are thought to control the regulation of genetic programs in normal physiology and cancer. Methylation (mono-, di-, and tri-methylation) on histone H3 lysine (K) 27 induces transcriptional repression, and thereby participates in controlling gene expression patterns. Enhancer of zeste (EZH) 2, a methyltransferase and component of the polycomb repressive complex 2 (PRC2), plays an essential role in the epigenetic maintenance of the H3K27me3 repressive chromatin mark. Abnormal EZH2 expression has been associated with various cancers including breast cancer. Here, we discuss the contribution of EZH2 and the PRC2 complex in controlling the H3K27 methylation status and subsequent consequences on genomic instability and the cell cycle in breast cancer cells. We also discuss distinct molecular mechanisms used by EZH2 to suppress BRCA1 functions.
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