Regulation of PSMA Expression by PSMA Promoter Enhancer

Prostate-specific membrane antigen has been shown to be increased severalfold in the expression in prostate cancer; its expression is suppressed by androgen. Currently, two regulatory elements controlling PSMA expression have been characterized. The proximal

Psma Prostate Cancer

Fig. 5. The regulation of PSMA in prostate cancer cells. Negative regulation by androgen receptor and positive regulation by Ca2+ is shown. Polyglutamated folates become enzymatically cleaved to deglu-tamated folates and glutamates. The folates can enter the cells through reduced folate-carrier (RFC) or folate-binding proteins (FBP). The glutamates produced by the PSMA-expressing cells can activate metabotrophic glutamate receptors, which can become activated and alter the resting membrane potential, which causes the efflux of Cl- ions and influx of Ca2+ ions to compensate for the damage of the cells. Ca2+ ions can modulate the expression level of PSMA in many ways. Increased Ca2+ concentration can activate inactive transcription factor NFATc1 (which is a transcriptional activator of PSMA enhancer [PSME]), or cause activation of calpain, which cleaves FLNa. Truncated FLNa binds to androgen receptor (AR) and localizes to the nucleus and suppresses AR-mediated transactivation. Normally, AR would sequester AP1 or tissue-specific transcription factors (e.g., SRY or SOX), causing inhibition of PSME.

Fig. 5. The regulation of PSMA in prostate cancer cells. Negative regulation by androgen receptor and positive regulation by Ca2+ is shown. Polyglutamated folates become enzymatically cleaved to deglu-tamated folates and glutamates. The folates can enter the cells through reduced folate-carrier (RFC) or folate-binding proteins (FBP). The glutamates produced by the PSMA-expressing cells can activate metabotrophic glutamate receptors, which can become activated and alter the resting membrane potential, which causes the efflux of Cl- ions and influx of Ca2+ ions to compensate for the damage of the cells. Ca2+ ions can modulate the expression level of PSMA in many ways. Increased Ca2+ concentration can activate inactive transcription factor NFATc1 (which is a transcriptional activator of PSMA enhancer [PSME]), or cause activation of calpain, which cleaves FLNa. Truncated FLNa binds to androgen receptor (AR) and localizes to the nucleus and suppresses AR-mediated transactivation. Normally, AR would sequester AP1 or tissue-specific transcription factors (e.g., SRY or SOX), causing inhibition of PSME.

1.2-kb PSMA enhancer (PSME) (57,58) (located within the third intron of FOLH1) renders the prostate-specific expression of PSMA. PSME is activated in a prostate-specific manner, negatively regulated by androgen receptor, and its expression is upregulated in prostate cancer. A detailed study showed that proximal 90 bp of PSME contained enhancer element with an AP3 site responsible for elevation of promoter activity of PSME beyond the basal level (59). Furthermore, recent work by this group has shown that Ca2+-dependent activation PSME transcription factor NFATc1 isoform binds to AP1. In the presence of the C a2+, NFATc1 protein gets dephosphorylated through C a2+-dependent calcineurin, which drives the translocation of NFAT protein to nucleus and activates the transcription of PSMA (Fig. 4).

Direct repeat regions of PSME harbors nine copies of SRY/SOX sites. SRY, SOX 7, and SOX 18 are reportedly expressed prostate cancer and prostate epithelial cells (60). SRY or SOX might interact with AR-DBD (androgen receptor DNA-binding domain), and as a result, AR sequesters these tissue-specific proteins, causing repression of PSME, which could partially explain the AR-mediated repression of PSME.

Ca2+ ions positively regulate PSMA expression. Ca2+ influx probably takes place through a CaT-like calcium channel, which is strikingly correlated with the malignancy of prostate cancer as well as PSMA expression (61). How could that start? The possible explanation could involve glutamate receptors. We have observed metabotropic glutamate receptors by gene-array analysis of LNCaP cells (Heston et al., unpublished observation). In prostate cancer cells, such receptors could get activated constitutively by free glutamates (an agonist to such a receptor) released as a byproduct of the folate hydrolase/NAALADase action of PSMA expressed on the cell surface (PSMA level is upregulated many-fold in prostate cancers) and can modulate the function of potassium and calcium channels, which might cause change in resting membrane potential. Such a change in membrane potential could cause oxidative damage to the cells, release of Cl- ions (62), and continuous influx of Ca2+ ions through calcium channels (to compensate for such change in membrane potential).

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