title: FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells.
abstract: TMPRSS2-ERG and other gene fusions involving ETS factors and genes with strong promoter elements are common in prostate cancer. Although ERG activation has been linked to invasive properties of prostate cancers, the precise mechanisms and pathways of ERG-mediated oncogenesis remain poorly understood. Here, we show that ERG knockdown in VCaP prostate cancer cells causes an activation of cell adhesion, resulting in strongly induced active beta(1)-integrin and E-cadherin expression as well as changes in WNT signaling. These observations were corroborated by data from ERG-overexpressing nontransformed prostate epithelial cells as well as gene expression data from clinical prostate cancer samples, which both indicated a link between ERG and epithelial-to-mesenchymal transition (EMT). Upregulation of several WNT pathway members was seen in ERG-positive prostate cancers, with frizzled-4 (FZD4) showing the strongest overexpression as verified by both reverse transcription-PCR and immunostaining. Both ERG knockin and knockdown modulated the levels of FZD4 expression. FZD4 silencing could mimic the ERG knockdown phenotype by inducing active beta(1)-integrin and E-cadherin expression, whereas FZD4 overexpression reversed the phenotypic effects seen with ERG knockdown. Taken together, our results provide mechanistic insights to ERG oncogenesis in prostate cancer, involving activation of WNT signaling through FZD4, leading to cancer-promoting phenotypic effects, including EMT and loss of cell adhesion.
authors: Medical Biotechnology, VTT Technical Research Centre of Finland, Finland.
authors: Santosh
authors: S
authors: Gupta
authors: Kristiina
authors: K
authors: Iljin
authors: Henri
authors: H
authors: Sara
authors: John Patrick
authors: JP
authors: Mpindi
authors: Tuomas
authors: T
authors: Mirtti
authors: Paula
authors: P
authors: Vainio
authors: Juha
authors: J
authors: Rantala
authors: Kalle
authors: K
authors: Alanen
authors: Matthias
authors: M
authors: Nees
authors: Olli
authors: O
authors: Kallioniemi
mesh_terms: D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000473:pathology; D051157:Frizzled Receptors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008648:Mesoderm / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D000071230:Transcriptional Regulator ERG; D014162:Transfection; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D015820:Cadherins; C072312:ERG protein, human; C402930:FZD4 protein, human; D051157:Frizzled Receptors; D019012:Integrin beta1; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051153:Wnt Proteins