Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models

Carcinogenesis. 2012 Dec;33(12):2558-67. doi: 10.1093/carcin/bgs285. Epub 2012 Oct 1.

Abstract

Approximately half of prostate cancers (PCa) carry TMPRSS2-ERG translocations; however, the clinical impact of this genomic alteration remains enigmatic. Expression of v-ets erythroblastosis virus E26 oncogene like (avian) gene (ERG) promotes prostatic epithelial dysplasia in transgenic mice and acquisition of epithelial-to-mesenchymal transition (EMT) characteristics in human prostatic epithelial cells (PrECs). To explore whether ERG-induced EMT in PrECs was associated with therapeutically targetable transformation characteristics, we established stable populations of BPH-1, PNT1B and RWPE-1 immortalized human PrEC lines that constitutively express flag-tagged ERG3 (fERG). All fERG-expressing populations exhibited characteristics of in vitro and in vivo transformation. Microarray analysis revealed >2000 commonly dysregulated genes in the fERG-PrEC lines. Functional analysis revealed evidence that fERG cells underwent EMT and acquired invasive characteristics. The fERG-induced EMT transcript signature was exemplified by suppressed expression of E-cadherin and keratins 5, 8, 14 and 18; elevated expression of N-cadherin, N-cadherin 2 and vimentin, and of the EMT transcriptional regulators Snail, Zeb1 and Zeb2, and lymphoid enhancer-binding factor-1 (LEF-1). In BPH-1 and RWPE-1-fERG cells, fERG expression is correlated with increased expression of integrin-linked kinase (ILK) and its downstream effectors Snail and LEF-1. Interfering RNA suppression of ERG decreased expression of ILK, Snail and LEF-1, whereas small interfering RNA suppression of ILK did not alter fERG expression. Interfering RNA suppression of ERG or ILK impaired fERG-PrEC Matrigel invasion. Treating fERG-BPH-1 cells with the small molecule ILK inhibitor, QLT-0267, resulted in dose-dependent suppression of Snail and LEF-1 expression, Matrigel invasion and reversion of anchorage-independent growth. These results suggest that ILK is a therapeutically targetable mediator of ERG-induced EMT and transformation in PCa.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azo Compounds / pharmacology
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition
  • Humans
  • Lymphoid Enhancer-Binding Factor 1 / physiology
  • Male
  • Mice
  • Neoplasm Invasiveness
  • Prostatic Neoplasms / pathology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / physiology*
  • Pyrazoles / pharmacology
  • Snail Family Transcription Factors
  • Trans-Activators / physiology*
  • Transcription Factors / physiology
  • Transcriptional Regulator ERG

Substances

  • Azo Compounds
  • ERG protein, human
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • Pyrazoles
  • QLT 0267
  • Snail Family Transcription Factors
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Regulator ERG
  • integrin-linked kinase
  • Protein-Serine-Threonine Kinases