Abstract
Epigenetic modifications such as histone methylation play an important role in human cancer metastasis. Enhancer of zeste homolog 2 (EZH2), which encodes the histone methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed widely in breast and prostate cancers and epigenetically silences tumor suppressor genes. Expression levels of the novel tumor and metastasis suppressor Raf-1 kinase inhibitor protein (RKIP) have been shown to correlate negatively with those of EZH2 in breast and prostate cell lines as well as in clinical cancer tissues. Here, we show that the RKIP/EZH2 ratio significantly decreases with the severity of disease and is negatively associated with relapse-free survival in breast cancer. Using a combination of loss- and gain-of-function approaches, we found that EZH2 negatively regulated RKIP transcription through repression-associated histone modifications. Direct recruitment of EZH2 and suppressor of zeste 12 (Suz12) to the proximal E-boxes of the RKIP promoter was accompanied by H3-K27-me3 and H3-K9-me3 modifications. The repressing activity of EZH2 on RKIP expression was dependent on histone deacetylase promoter recruitment and was negatively regulated upstream by miR-101. Together, our findings indicate that EZH2 accelerates cancer cell invasion, in part, via RKIP inhibition. These data also implicate EZH2 in the regulation of RKIP transcription, suggesting a potential mechanism by which EZH2 promotes tumor progression and metastasis.
Highlights
Cancer cells are characterized by an unbalanced and dramatically altered epigenetic state compared with normal counterparts
We further show that the repressive activity of Enhancer of zeste homolog 2 (EZH2) on Raf-1 kinase inhibitor protein (RKIP) transcription required the presence of the EMT inducer Snail
RKIP expression negatively correlates with EZH2 levels in prostate human cancer samples and the RKIP/EZH2 ratio predicts relapse-free breast cancer survival
Summary
Cancer cells are characterized by an unbalanced and dramatically altered epigenetic state compared with normal counterparts. Histone modifications and DNA methylation are among the most studied epigenetic mechanisms that control the accessibility of target gene promoters to positive or negative transcriptional signals and regulate gene expression. Epigenetic alterations related to transcriptional inactivation of tumor suppressor genes form part of a regulatory mecha-. Authors' Affiliations: 1Department of Biochemistry and Cancer Biology, College of Medicine, Health Science Campus, University of Toledo, Toledo, Ohio; 2Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, California; 3Department of Chemistry, University of Connecticut, Storrs, Connecticut; 4Department of Urology and Pathology, University of Michigan, Ann Arbor, Michigan; and 5Department of Pathology, Faculty of Medicine, Kuwait University Health Sciences Centre, Safat, Kuwait. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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