Abstract
Prostate cancer (PCa) remains one of the most frequently diagnosed cancers in men in Western countries. Since noticeable geographic variations have been observed in the incidence of PCa, studies have implicated a “Western” diet in the development of PCa. Because of this and the nature of PCa, which is typically diagnosed in the elderly population wth a relatively slower rate of growth and progression, chemoprevention through dietary compounds promises to be an effective approach for PCa. Resveratrol (Res) (3,5,4’-trihydroxy-trans-stilbene), a natural compound found in grapes, peanuts and berries, is one of the most promising diet-derived chemopreventive agent with potential chemotherapeutic capacities. There is growing evidence that Res may contribute to chromatin remodeling that are important in cancer progression. Metastasis-associated protein 1 (MTA1), which is overexpressed in many cancer, is a part of nucleosome remodeling and deacetylation (NuRD) complex that mediates posttranslational modifications of histones and nonhistone proteins resulting in transcriptional gene silencing. The complex also contains histone deacetylases 1 and 2 (HDAC1 and 2). MTA1/HDAC1 subunit plays an essential role in governing deacetylation of histones and other proteins. We recently demonstrated that Res down-regulated MTA1 protein levels in PCa cells, leading to destabilization of MTA1/HDAC1/NuRD complex thus allowing acetylation and activation of tumor suppressor p53. MTA1 silencing by RNA interference further sensitized PCa cells to Res-dependent p53 acetylation, transcriptional activation of p21 and Bax and apoptosis. To further understand Res-induced MTA1-associated epigenetic alterations, we analyzed MTA1-associated and Res-induced microRNAs expression changes using LNCaP cells expressing and silenced for MTA1. We found that expression of 13 miRNA was increase, and 17 miRNAs was decreased in cells silenced for MTA1 gene. In addition, 28 miRNAs were overexpresed, and 23 miRNAs were degreased under Res treatment. Among these miRNAs were some with well-characterized cancer association, such as let-7g, miR-16-2, miR-26a, miR-20b, miR-27a, miR-22, miR-34a, miR-92 and others. The predicted targets for the overlapping miRNAs are significantly enriched for protein-coding oncogenes and tumor suppressors. Our data indicate that MTA1-associated miRNAs are involved in Res-mediated anticancer and preventive effects in prostate cancer.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A24.
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