Correction: CDKN1C (p57) Is a Direct Target of EZH2 and Suppressed by Multiple Epigenetic Mechanisms in Breast Cancer Cells

Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore.
PLoS ONE (Impact Factor: 3.53). 02/2009; 4(4):e5011. DOI: 10.1371/journal.pone.0005011
Source: PubMed

ABSTRACT 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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Available from: RK Murthy Karuturi, Aug 23, 2015
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    • "This protein may maintain non-proliferative or quiescent state of a cell for throughout its life. It also acts as a tumor suppressor gene and is suppressed by multiple epigenetic mechanisms in breast cancers [114]. In support of this behavior, non-classical monocytes also express increased level of Notch4 and HES4 (hairy and enhancer of split 4). "
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    • "EZH2 is a crucial component of polycomb repressor complex 2 (PRC2), and its oncogenic function is thought mainly to be mediated through its gene silencing activity. A number of putative tumor suppressors, including INK4A/ARF (Agherbi et al., 2009; Bracken et al., 2007), p57 (Yang et al., 2009), RUNX3 (Fujii et al., 2008), Bim (Wu et al., 2010), and FBXO32 (Tan et al., 2007; Wu et al., 2010), have been found to be EZH2 targets. In breast cancers, higher EZH2 expression is known to be more associated with aggressive basal-like subtype and poor metastasis-free survival (Kleer et al., 2003; Puppe et al., 2009). "
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    • "Moreover, the p53- induced Cip/Kip CDK inhibitors, which act at both the G1/S and the G2/M transition, are also regulated by PcG proteins. EZH2 was reported to bind and repress the p57 Kip2 locus in breast cancer cells (Yang et al., 2009), whereas p21 Cip1 is repressed by BMI1 or its paralog PCFG1 (Fasano et al., 2007; Gong et al., 2006). Accordingly, knockdown of p21 Cip1 partially rescues the proliferative defects and the decreased frequency and size of Bmi1-deficient neurospheres. "
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