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Oncotarget. 2015 Dec 1;6(38):41045-55. doi: 10.18632/oncotarget.5728.

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

Author information

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.

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.

KEYWORDS:

EZH2; MALAT1; Polycomb repressive complex 2 (PRC2); castration-resistant prostate cancer (CRPC)

PMID:
26516927
PMCID:
PMC4747388
DOI:
10.18632/oncotarget.5728
[Indexed for MEDLINE]
Free PMC Article

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