LncRNA MALAT1 enhances oncogenic activities of EZH2 in castrationresistant prostate cancer

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

Research output: Contribution to journalArticle

99 Citations (Scopus)

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

Fingerprint

Prostatic Neoplasms
Castration
Enhancer of Zeste Homolog 2 Protein
Long Noncoding RNA
RNA
Immunoprecipitation
Heterografts
Genes
Meta-Analysis
Cell Culture Techniques
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

LncRNA MALAT1 enhances oncogenic activities of EZH2 in castrationresistant prostate cancer. / Wang, Dejie; Ding, Liya; Wang, Liguo; Zhao, Yu; Sun, Zhifu D; Karnes, Robert Jeffrey; Zhang, Jun; Huang, Haojie.

In: Oncotarget, Vol. 6, No. 38, 2015, p. 41045-41055.

Research output: Contribution to journalArticle

@article{8ea4a642627741daab97f8ec8cd893c2,
title = "LncRNA MALAT1 enhances oncogenic activities of EZH2 in castrationresistant 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 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.",
keywords = "Castration-resistant prostate cancer (CRPC), EZH2, MALAT1, Polycomb repressive complex 2 (PRC2)",
author = "Dejie Wang and Liya Ding and Liguo Wang and Yu Zhao and Sun, {Zhifu D} and Karnes, {Robert Jeffrey} and Jun Zhang and Haojie Huang",
year = "2015",
doi = "10.18632/oncotarget.5728",
language = "English (US)",
volume = "6",
pages = "41045--41055",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "38",

}

TY - JOUR

T1 - LncRNA MALAT1 enhances oncogenic activities of EZH2 in castrationresistant prostate cancer

AU - Wang, Dejie

AU - Ding, Liya

AU - Wang, Liguo

AU - Zhao, Yu

AU - Sun, Zhifu D

AU - Karnes, Robert Jeffrey

AU - Zhang, Jun

AU - Huang, Haojie

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Castration-resistant prostate cancer (CRPC)

KW - EZH2

KW - MALAT1

KW - Polycomb repressive complex 2 (PRC2)

UR - http://www.scopus.com/inward/record.url?scp=84951193344&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84951193344&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.5728

DO - 10.18632/oncotarget.5728

M3 - Article

C2 - 26516927

AN - SCOPUS:84951193344

VL - 6

SP - 41045

EP - 41055

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 38

ER -