%0 Journal Article
%T miR-204 Shifts the Epithelial to Mesenchymal Transition in Concert with the Transcription Factors RUNX2, ETS1, and cMYB in Prostate Cancer Cell Line Model
%A Krassimira Todorova
%A Diana Zasheva
%A Kristiyan Kanev
%A Soren Hayrabedyan
%J Journal of Cancer Research
%D 2014
%R 10.1155/2014/840906
%X Epithelial to mesenchymal transition is an essential step in advanced cancer development. Many master transcription factors shift their expression to drive this process, while noncoding RNAs families like miR-200 are found to restrict it. In this study we investigated how the tumor suppressor miR-204 and several transcription factors modulate main markers of mesenchymal transformation like E- and N-cadherin, SLUG, VEGF, and SOX-9 in prostate cancer cell line model (LNCaP, PC3, VCaP, and NCI-H660). We found that SLUG, E-cadherin, and N-cadherin are differentially modulated by miR-204, using miR-204 specific mimics and inhibitors and siRNA gene silencing (RUNX2, ETS-1, and cMYB). The genome perturbation associated TMPRSS2-ERG fusion coincided with shift from tumor-suppressor to tumor-promoting activity of this miRNA. The ability of miR-204 to suppress cancer cell viability and migration was lost in the fusion harboring cell lines. We found differential E-cadherin splicing corroborating to miR-204 modulatory effects. RUNX2, ETS1, and cMYB are involved in the regulation of E-cadherin, N-cadherin, and VEGFA expression. RUNX2 knockdown results in SOX9 downregulation, while ETS1 and cMYB silencing result in SOX9 upregulation in VCaP cells. Their expression was found to be also methylation dependent. Our study provides means for understanding cancer heterogeneity in regard to adapted therapeutic approaches development. 1. Introduction Prostate cancer is one of the most common malignancies and the second leading cause of death from cancer in men. Androgen receptor (AR) is paramount for the lineage-specific differentiation of the prostate, inducing the expression of prostate-specific genes, such as PSA and TMPRSS2, and maintaining the differentiated prostate epithelial phenotype [1]. Cellular dedifferentiation and epithelial to mesenchymal transition (EMT), by contrast, are a hallmark of malignant transformation and metastatic disease. In this process the reexpression of conserved developmental programs plays a key role [2]. Chromosomal rearrangements fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG occur in approximately 50% of prostate cancers and more than 90% of them overexpress ERG [3]. TMPRSS2-ERG is crucial for cancer progression by disrupting lineage-specific differentiation of the prostate and potentiating the histone methyltransferase EZH2-mediated dedifferentiation program. ERG disrupts AR signalling by inhibiting AR expression, binding to and inhibiting AR activity at gene-specific loci, and inducing repressive
%U http://www.hindawi.com/journals/jcr/2014/840906/