title: Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models.
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.
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia,  Canada V5Z 1L3.
authors.forename: Daiana D
authors.initials: DD
authors.lastname: Becker-Santos
authors.forename: Yubin
authors.initials: Y
authors.lastname: Guo
authors.forename: Mazyar
authors.initials: M
authors.lastname: Ghaffari
authors.forename: Elaine D
authors.initials: ED
authors.lastname: Vickers
authors.forename: Melanie
authors.initials: M
authors.lastname: Lehman
authors.forename: Manuel
authors.initials: M
authors.lastname: Altamirano-Dimas
authors.forename: Arusha
authors.initials: A
authors.lastname: Oloumi
authors.forename: Junya
authors.initials: J
authors.lastname: Furukawa
authors.forename: Manju
authors.initials: M
authors.lastname: Sharma
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cox
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000502:physiology; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D000071250:Snail Family Transcription Factors; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D000071230:Transcriptional Regulator ERG; D000099200:Scaffold Protein ILK
chemical_list: D001391:Azo Compounds; D051821:Lymphoid Enhancer-Binding Factor 1; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D000071250:Snail Family Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D000099200:Scaffold Protein ILK; C072312:ERG protein, human; C497573:LEF1 protein, human; C552362:QLT 0267