Regulation of the PTEN promoter by statins and SREBP

Abstract

Germline mutations in the tumor-suppressor gene PTEN predispose to heritable breast cancer. The transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. We previously demonstrated that lovastatin may signal through PPARgamma and directly upregulate PTEN expression at the transcriptional level. In our current study, we show that simvastatin, pravastatin and fluvastatin can induce PTEN expression in a dose-dependent manner. This resulted from an increase in PTEN mRNA indicating transcriptional upregulation. In addition, we observed, for the first time, that upregulation of sterol response element-binding protein (SREBP), known to induce PPARgamma expression, can increase PTEN expression. Using reporter assays, we observed that both the statins and SREBP could specifically induce PPARgamma-mediated transcription. However, the statins do not appear to signal through SREBP. Furthermore, our results indicate that SREBP utilizes PPARgamma's transcriptional activity to induce PTEN transcription, whereas the statins signal through PPARgamma's protein activity to upregulate PTEN expression. Overall, our observations suggest that statins signal through another transcription factor, in a PPARgamma-dependent manner, which in turn induces PTEN transcription. We, therefore, studied the full-length PTEN promoter through serial deletion reporter assays and electromobility shift assays and identified a region between -854 and -791 that binds an as-yet-unidentified transcription factor, through which the statins induce PTEN expression. Since PTEN is constitutively active, our data indicate it may be worthwhile to examine statin and SREBP stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies in cancer, diabetes mellitus and cardiovascular disease.

Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers

“…Reporter constructs included a full-length (À1344 to À1) and truncated (À1344 to À1001) PTEN promoter (Teresi et al, 2008). Both PTEN promoters, the full-length as well as the À1344 to À1001 segments, could be inhibited by DHT and activated by Casodex in AR-positive LNCaP and C4-2 cells (Figure 1c).…”

“…We generated PTEN promoters tagged with the firefly luciferase gene, as described in our previous study (Teresi et al, 2008). Reporter gene activity was determined by dual luciferase assay using a luciferase enzyme assay system (Promega, Madison, WI, USA).…”

Mitophagy Is Required for Acute Cardioprotection by Simvastatin

“…Several studies have implicated phophoinositide 3-kinase (PI3K), protein kinase B (Akt), and endothelial nitric oxide synthase (eNOS) upregulation in the mechanism of cardioprotection [reviewed in Ludman et al (30)], which is consistent with the notion that signaling through Akt and mammalian target of rapamycin (mTOR) is generally regarded as a prosurvival pathway. In contrast, others have reported that acute statin administration upregulates phosphatase and tensin homolog (PTEN), which would antagonize the Akt/mTOR signaling pathway (11,54). PTEN does so by dephosphorylating phosphatidylinositol (3,4,5)-triphosphate (PIP 3 ), effectively blunting Akt activation.…”

Is immunity a mechanism contributing to statin-induced diabetes?

“…65 This builds on a very interesting connection between statin-induced increases in PTEN transcription via a sterol response element-binding protein (SREBP) pathway. 66 PTEN is a component in cell cycle regulation and inhibits transduction of the insulin signal by converting phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ) back to PIP 2 ( Fig. 1), preventing activation of phosphoinositide-dependent kinase-1 (PDK1) and subsequent phosphorylation of AKT.…”