Presentation Abstract

Abstract Number: 4057
Presentation Title: Negative regulation of prostate specific membrane antigen by androgen is mediated by TMPRSS2-ERG gene fusion in VCaP prostate cancer cells
Presentation Time: Tuesday, Apr 20, 2010, 2:00 PM - 5:00 PM
Location: Exhibit Hall A-C, Poster Section 8
Poster Section: 8
Poster Board Number: 1
Author Block: Lihong Yin1, Pravin Rao1, Jianghua Wang2, Michael Ittmann2, Warren D.W. Heston1. 1Cleveland Clinic, Cleveland, OH; 2Baylor College of Medicine, Houston, TX
Abstract Body: Prostate specific membrane antigen (PSMA) is a type II transmembrane glycoprotein over-expressed in prostate carcinoma. Elevated PSMA expression has been correlated with aggressive disease and risk of early recurrence after radical prostatectomy. This molecule is also expressed in the neovasculature of multiple nonprostate solid tumors. Consequently, this unique cell marker has been targeted for diagnosis and therapy of prostate cancer (PCa) and other malignancies. Recently studies have shown that a significant fraction of PCa harbor a signature gene fusion between the androgen-responsive TMPRSS2 gene and transcription factors in the ETS family - most commonly ERG. The TMPRSS2-ERG fusion is likely the cause for over-expression of ERG in PCa. PSMA, unlike ERG, is negatively regulated by androgen. Elucidation of the relationship between TMPRSS2 gene fusions and PSMA expression could reveal mechanisms to alter PSMA expression and disease course. The purpose of this investigation was to determine whether PSMA gene expression could be regulated by the TMPRSS2-ERG fusion in prostate cancer cells.
We employed VCaP cells, which harbor TMPRSS2-ERG fusion, and LNCaP cells, which lack the fusion. Our data showed that after 24h androgen R1881 treatment, ERG and TMPRSS2-ERG mRNA level were increased in VCaP cells and unchanged in LNCaP cells. PSMA and androgen receptor (AR) mRNA level were dramatically decreased in VCaP cells and only modestly decreased in LNCaP cells. Treatment with the androgen antagonist flutamide partially restored PSMA and AR expression in androgen-treated VCaP cells. Knocking down ERG by siRNA in VCaP cells enhances PSMA expression both in the presence and absence of R1881. When LNCaP cells transfected with TMPRSS2-ERG fusion transcripts, PSMA was down-regulated both in the presence or absence of R1881. Using PSMA-based luciferase reporter assays, we found TMPRSS2-ERG fusion can inhibit PSMA activity at the transcriptional level. Our data indicated that negative regulation of PSMA by androgen is mediated by TMPRSS2-ERG gene fusion in VCaP prostate cancer cells.