Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer

Gang Ren, Stavroula Baritaki, Himangi Marathe, Jingwei Feng, Sungdae Park, Sandy Beach, Peter S. Bazeley, Anwar B. Beshir, Gabriel Fenteany, Rohit Mehra, Stephanie Daignault, Fahd Al-Mulla, Evan Keller, Ben Bonavida, Ivana De La Serna, Kam C. Yeung

Research output: Contribution to journalArticlepeer-review

153 Citations (Scopus)

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 repressionassociated 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.

Original languageEnglish
Pages (from-to)3091-3104
Number of pages14
JournalCancer Research
Volume72
Issue number12
DOIs
Publication statusPublished - 15 Jun 2012

Fingerprint Dive into the research topics of 'Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer'. Together they form a unique fingerprint.

Cite this