Resveratrol and pterostilbene epigenetically restore PTEN expression by targeting OncomiRs of the miR-17 family in prostate cancer

Authors: DHAR, SWATI - University Of Mississippi Medical Center; KUMAR, AVINASH - University Of Mississippi Medical Center; Rimando, Agnes; ZHANG, XU - University Of Mississippi Medical Center; LEVENSON, ANAIT - University Of Mississippi Medical Center

Submitted to: Oncotarget
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/24/2015
Publication Date: 8/6/2015
Publication URL: http://handle.nal.usda.gov/10113/62329
Citation: Dhar, S., Kumar, A., Rimando, A.M., Zhang, X., Levenson, A.S. 2015. Resveratrol and pterostilbene epigenetically restore PTEN expression by targeting OncomiRs of the miR-17 family in prostate cancer. Oncotarget. 6(29):27214-27226.

Interpretive Summary: The polymeric molecule RNA are involved in coding, regulation, and expression of genes, but small fragments of RNA, called micro-RNA (miRNA), are non-coding and their main function is to downregulate gene expression in a variety of manners. In the recent years, the role of miRNAs in cancer has become clearer and their utilization as potential biomarkers and therapeutic targets has also gained ground. In our previous study, we reported that the phenolic compound resveratrol downregulates tumour-promoting members of the miR-17 family, which are over-expressed in prostate cancer. These miRNAs target the phosphatase and tensin homolog (PTEN), which is a tumour-suppressor gene. In the present study we investigated whether resveratrol and its derivative pterostilbene modulate the miRNA-mediated regulation of PTEN. We show that both compounds decrease the levels of small RNA fragments, thereby up-regulating their target PTEN in prostate cancer cells. Further, in animal study, pterostilbene, through downregulation of expression of the small RNA fragments miR-17-5p and miR-106a-5p, both in tumors and systemic circulation, rescued PTEN leading to reduced tumor growth in the animals. Our findings implicate dietary stilbenes as an attractive miRNA-mediating chemopreventive and therapeutic strategy. Our study further shows that circulating miRNAs are potential chemopreventive and predictive biomarkers for clinical development in prostate cancer.

Technical Abstract: 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 also 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 both 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.