TMPRSS2-ERG gene fusions induce prostate tumorigenesis by modulating microRNA miR-200c

J. Kim, L. Wu, J. C. Zhao, H. J. Jin, J. Yu*

*Corresponding author for this work

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Chromosomal translocations that juxtapose the androgen-sensitive transmembrane protease, serine 2 (TMPRSS2) gene promoter to the oncogenic ETS-family transcription factor ERG result in excessive ERG overexpression in approximately 50% of prostate cancer (PCa) patients. Although numerous studies have investigated ERG-downstream genes, such studies have not attempted to examine miRNAs, which however are emerging to be important regulators of cancer. Through bioinformatics analysis of ChIP-Seq ERG data and miRNA expression profiling data we nominated miR-200c as a direct target of ERG. Experimentation of PCa cells with ERG overexpression or knockdown demonstrated that ERG directly repressed miR-200c expression by physically binding to the erythroblast transformation-specific (ETS) motif within its promoter. Consequently, miR-200c was downregulated in ERG-positive PCa, and miR-200c target gene expression was restored. In addition, the expression pattern of miR-200c target genes predicted ERG status in clinical PCa specimens. Furthermore, miR-200c was found to be important in modulating ZEB1 upregulation by ERG. Most importantly, miR-200c reconstitution fully reversed ERG-induced epithelial-to-mesenchymal transition (EMT), cell migration and invasion. Therefore, our study report miR-200c as the first miRNA target of ERG and a critical inhibitor of PCa cell motility. Therapeutic delivery of miR-200c may provide personalized treatment for patients with the molecular subtype of PCa that harbors TMPRSS2-ERG gene fusions.

Original languageEnglish (US)
Pages (from-to)5183-5192
Number of pages10
JournalOncogene
Volume33
Issue number44
DOIs
StatePublished - Nov 4 2013

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Keywords

  • EMT
  • TMPRSS2-ERG
  • miR-200c
  • prostate cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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