Prostate specific membrane
antigen (PSMA) is overexpressed in prostatic
adenocarcinoma (CaP), and its expression is negatively regulated by
androgen stimulation. However, it is still unclear which factors are involved in this downregulation. TMPRSS2-ERG fusion is the most common known gene rearrangement in prostate
carcinoma.
Androgen stimulation can increase expression of the TMPRSS2-ERG fusion in fusion positive
prostate cancer cells. The purpose of this investigation is to determine whether PSMA expression can be regulated by the TMPRSS2-ERG gene fusion. We employed two PSMA positive cell lines: VCaP cells, which harbor TMPRSS2-ERG fusion, and LNCaP cells, which lack the fusion. After 24 hours of
androgen treatment, TMPRSS2-ERG
mRNA level was increased in VCaP cells. PSMA
mRNA level was dramatically decreased in VCaP cells, while it only has moderate change in LNCaP cells. Treatment with the
androgen antagonist flutamide partially restored PSMA expression in
androgen-treated VCaP cells. Knocking down ERG by
siRNA in VCaP cells enhances PSMA expression both in the presence and absence of
synthetic androgen R1881. Overexpressing TMPRSS2-ERG fusions in LNCaP cells downregulated PSMA both in the presence or absence of
R1881, while overexpressing wild type ERG did not. Using PSMA-based
luciferase reporter assays, we found TMPRSS2-ERG fusion can inhibit PSMA activity at the transcriptional level. Our data indicated that downregulation of PSMA in
androgen-treated VCaP cells appears partially mediated by TMPRSS2-ERG gene fusion.