Article

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.

Download full-text

Full-text

Available from: RK Murthy Karuturi, Aug 23, 2015
1 Follower
 · 
295 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Classical and non-classical monocytes are two well-defined subsets of monocytes displaying distinct roles. They differentially express numerous genes relevant to their primary role. Using five independent transcriptomic microarray datasets, we ruled out several inconsistent genes and identified common genes consistently overexpressed either in classical or non-classical monocytes. One hundred and eight genes were significantly increased in classical monocytes and are involved in bacterial defense, inflammation and atherosclerosis. Whereas the 74 genes overexpressed in non-classical monocytes are involved in cytoskeletal dynamics and invasive properties for enhanced motility and infiltration. These signatures unravel the biological functions of monocyte subsets. HIGHLIGHTS We compared five transcriptomic GEO datasets of human monocyte subsets. 108 genes in classical and 74 genes in non-classical monocytes are upregulated. Upregulated genes in classical monocytes support anti-bacterial and inflammatory responses. Upregulated genes in non-classical monocytes support patrolling and infiltration functions.
    International Reviews Of Immunology 04/2014; 33(6). DOI:10.3109/08830185.2014.902453 · 5.28 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Both EZH2 and NF-κB contribute to aggressive breast cancer, yet whether the two oncogenic factors have functional crosstalk in breast cancer is unknown. Here, we uncover an unexpected role of EZH2 in conferring the constitutive activation of NF-κB target gene expression in ER-negative basal-like breast cancer cells. This function of EZH2 is independent of its histone methyltransferase activity but requires the physical interaction with RelA/RelB to promote the expression of NF-κB targets. Intriguingly, EZH2 acts oppositely in ER-positive luminal-like breast cancer cells and represses NF-κB target gene expression by interacting with ER and directing repressive histone methylation on their promoters. Thus, EZH2 functions as a double-facet molecule in breast cancers, either as a transcriptional activator or repressor of NF-κB targets, depending on the cellular context. These findings reveal an additional mechanism by which EZH2 promotes breast cancer progression and underscore the need for developing context-specific strategy for therapeutic targeting of EZH2 in breast cancers.
    Molecular cell 09/2011; 43(5):798-810. DOI:10.1016/j.molcel.2011.08.011 · 14.46 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polycomb Group (PcG) proteins are transcriptional repressors that epigenetically modify chromatin and participate in the establishment and maintenance of cell fates. These proteins play important roles in both stem cell self-renewal and in cancer development. Our understanding of their mechanism of action has greatly advanced over the past 10 years, but many unanswered questions remain. In this review, we present the currently available experimental data that connect PcG protein function with some of the key processes which govern somatic stem cell activity. We also highlight recent studies suggesting that a delicate balance in PcG gene dosage is crucial for proper stem cell homeostasis and prevention of cancer stem cell development.
    Cell stem cell 09/2010; 7(3):299-313. DOI:10.1016/j.stem.2010.08.002 · 22.15 Impact Factor
Show more