Oncotarget

Research Papers:

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

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

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Oncotarget. 2015; 6:41045-41055. https://doi.org/10.18632/oncotarget.5728

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Abstract

Dejie Wang1,2,3,*, Liya Ding1,*, Liguo Wang4, Yu Zhao1, Zhifu Sun4, R. Jeffrey Karnes2,3, Jun Zhang5, Haojie Huang1,2,3

1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

2Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

3Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

4Department of Medical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA

5Department 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.


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