title: Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer.
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.
authors.affiliation: Department of Biochemistry and Cancer Biology, College of Medicine, Health Science Campus, University of Toledo, Toledo, Ohio, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Ren
authors.forename: Stavroula
authors.initials: S
authors.lastname: Baritaki
authors.forename: Himangi
authors.initials: H
authors.lastname: Marathe
authors.forename: Jingwei
authors.initials: J
authors.lastname: Feng
authors.forename: Sungdae
authors.initials: S
authors.lastname: Park
authors.forename: Sandy
authors.initials: S
authors.lastname: Beach
authors.forename: Peter S
authors.initials: PS
authors.lastname: Bazeley
authors.forename: Anwar B
authors.initials: AB
authors.lastname: Beshir
authors.forename: Gabriel
authors.initials: G
authors.lastname: Fenteany
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.forename: Stephanie
authors.initials: S
authors.lastname: Daignault
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.forename: Evan
authors.initials: E
authors.lastname: Keller
authors.forename: Ben
authors.initials: B
authors.lastname: Bonavida
authors.forename: Ivana
authors.initials: I
authors.lastname: de la Serna
authors.forename: Kam C
authors.initials: KC
authors.lastname: Yeung
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D049488:Phosphatidylethanolamine Binding Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006657:Histones; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D034741:RNA, Small Interfering; C430461:SUZ12 protein, human; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2