LncRNA MALAT1 enhances oncogenic activities of EZH2 in castrationresistant prostate cancer

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

Research output: Contribution to journalArticle

110 Scopus citations

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 antibodybased 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 RTqPCR 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.

Original languageEnglish (US)
Pages (from-to)41045-41055
Number of pages11
JournalOncotarget
Volume6
Issue number38
DOIs
StatePublished - 2015

Keywords

  • Castration-resistant prostate cancer (CRPC)
  • EZH2
  • MALAT1
  • Polycomb repressive complex 2 (PRC2)

ASJC Scopus subject areas

  • Oncology

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