Resveratrol and pterostilbene epigenetically restore PTEN expression by targeting oncomiRs of the miR-17 family in prostate cancer
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Swati Dhar1, Avinash Kumar1, Agnes M. Rimando2, Xu Zhang3, Anait S. Levenson1,4
1Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi, USA
2United States Department of Agriculture, Agricultural Research Service, Natural Products Utilization Research Unit, University, Mississippi, USA
3Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, Mississippi, USA
4Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi, USA
Anait S. Levenson, e-mail: [email protected]
Keywords: oncomiRs, prostate cancer epigenetics, PTEN, pterostilbene, resveratrol
Received: July 07, 2015 Accepted: July 24, 2015 Published: August 06, 2015
In recent years, not only has the role of miRNAs in cancer become increasingly clear but also their utilization as potential biomarkers and therapeutic targets has gained ground. Although the importance of dietary stilbenes such as resveratrol and pterostilbene as anti-cancer agents is well recognized, our understanding of their miRNA-targeting capabilities is still limited. In our previous study, we reported that resveratrol downregulates PTEN-targeting members of the oncogenic miR-17 family, which are overexpressed in prostate cancer. This study investigates the resveratrol and pterostilbene induced miRNA-mediated regulation of PTEN in prostate cancer. Here, we show that both compounds decrease the levels of endogenous as well as exogenously expressed miR-17, miR-20a and miR-106b thereby upregulating their target PTEN. Using functional luciferase reporter assays, we demonstrate that ectopically expressed miR-17, miR-20a and miR-106b directly target PTEN 3’UTR to reduce its expression, an effect rescued upon treatment with resveratrol and pterostilbene. Moreover, while stable lentiviral expression of miR-17/106a significantly decreased PTEN mRNA and protein levels and conferred survival advantage to the cells, resveratrol and more so pterostilbene was able to dramatically suppress these effects. Further, pterostilbene through downregulation of miR-17-5p and miR-106a-5p expression both in tumors and systemic circulation, rescued PTEN mRNA and protein levels leading to reduced tumor growth in vivo. Our findings implicate dietary stilbenes as an attractive miRNA-mediated chemopreventive and therapeutic strategy, and circulating miRNAs as potential chemopreventive and predictive biomarkers for clinical development in prostate cancer.
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