Regulation of the PTEN promoter by statins and SREBP.
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.
Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Rosemary E
RE
Teresi
Sarah M
SM
Planchon
Kristin A
KA
Waite
Charis
C
Eng
D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D019821:Simvastatin / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D047495:PPAR gamma; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D000077340:Fluvastatin; D019821:Simvastatin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017035:Pravastatin