title: LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer.
abstract: The Polycomb protein enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in advanced human prostate cancer (PCa), especially in lethal castration-resistant prostate cancer (CRPC). However, the signaling pathways that regulate EZH2 functions in PCa remain incompletely defined. Using EZH2 antibody-based RNA immunoprecipitation-coupled high throughput sequencing (RIP-seq), we demonstrated that EZH2 binds to MALAT1, a long non-coding RNA (lncRNA) that is overexpressed during PCa progression. GST pull-down and RIP assays demonstrated that the 3' end of MALAT1 interacts with the N-terminal of EZH2. Knockdown of MALAT1 impaired EZH2 recruitment to its target loci and upregulated expression of EZH2 repressed genes. Further studies indicated that MALAT1 plays a vital role in EZH2-enhanced migration and invasion in CRPC cell lines. Meta-analysis and RT-qPCR of patient specimens demonstrated a positive correlation between MALAT1 and EZH2 expression in human CRPC tissues. Finally, we showed that MALAT1 enhances expression of PRC2-independent target genes of EZH2 in CRPC cells in culture and patient-derived xenografts. Together, these data indicate that MALAT1 may be a crucial RNA cofactor of EZH2 and that the EZH2-MALAT1 association may provide a new avenue for development new strategies for treatment of CRPC.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Dejie
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Liya
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Medical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Liguo
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Medical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D020413:3' Untranslated Regions; C557041:MALAT1 long non-coding RNA, human; D062085:RNA, Long Noncoding; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: EZH2; MALAT1; Polycomb repressive complex 2 (PRC2); castration-resistant prostate cancer (CRPC)