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LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer

2015; Impact Journals LLC; Volume: 6; Issue: 38 Linguagem: Inglês

10.18632/oncotarget.5728

1949-2553

Dejie Wang, Liya Ding, Liguo Wang, Yu Zhao, Zhifu Sun, R. Jeffrey Karnes, Jun Zhang, Haojie Huang,

RNA Research and Splicing

// Dejie Wang 1, 2, 3, * , Liya Ding 1, * , Liguo Wang 4 , Yu Zhao 1 , Zhifu Sun 4 , R. Jeffrey Karnes 2, 3 , Jun Zhang 5 , Haojie Huang 1, 2, 3 1 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA 2 Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA 3 Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA 4 Department of Medical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA 5 Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA * These authors have contributed equally to this work Correspondence to: Haojie Huang, e-mail: huang.haojie@mayo.edu Keywords: MALAT1, EZH2, castration-resistant prostate cancer (CRPC), Polycomb repressive complex 2 (PRC2) Received: April 10, 2015 Accepted: September 20, 2015 Published: October 15, 2015 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.