The development of natural product agents with targeted strategies holds promise for enhanced anticancer therapy with reduced drug-associated side effects. Resveratrol found in red wine, has anticancer activity in various tumor types. We reported earlier on a new molecular target of resveratrol, the metastasis-associated protein 1 (MTA1), which is a part of nucleosome remodeling and deacetylation (NuRD) co-repressor complex that mediates gene silencing. We identified resveratrol as a regulator of MTA1/NuRD complex and re-activator of p53 acetylation in prostate cancer (PCa). In the current study, we addressed whether resveratrol analogues also possess the ability to inhibit MTA1 and to reverse p53 deacetylation. We demonstrated that pterostilbene (PTER), found in blueberries, had greater increase in MTA1-mediated p53 acetylation, confirming superior potency over resveratrol as dietary epigenetic agent. In orthotopic PCa xenografts, resveratrol and PTER significantly inhibited tumor growth, progression, local invasion and spontaneous metastasis. Furthermore, MTA1-knockdown sensitized cells to these agents resulting in additional reduction of tumor progression and metastasis. The reduction was dependent on MTA1 signaling showing increased p53 acetylation, higher apoptotic index and less angiogenesis in vivo in all xenografts treated with the compounds, and particularly with PTER. Altogether, our results indicate MTA1 as a major contributor in prostate tumor malignant progression, and support the use of strategies targeting MTA1. Our strong pre-clinical data indicate PTER as a potent, selective and pharmacologically safe natural product that may be tested in advanced PCa.

Our findings offer strong pre-clinical evidence for the utilization of dietary stilbenes, particularly 3M-Res, as novel, potent, effective chemopreventive agents in PCa.

Metastasis-associated protein 1 (MTA1), a negative epigenetic modifier, plays a critical role in prostate cancer (PCa) progression. We hypothesized that MTA1 overexpression in primary tumor tissues can predict PCa aggressiveness and metastasis. Immunohistochemical staining of MTA1 was done on archival PCa specimens from University of Mississippi Medical Center and University of Iowa. We found that nuclear MTA1 overexpression was positively correlated with the severity of disease progression reaching its highest levels in metastatic PCa. Nuclear MTA1 overexpression was significantly associated with Gleason > 7 tumors in African Americans but not in Caucasians. It was also a predictor of recurrent disease. We concluded that MTA1 nuclear overexpression may be a prognostic indicator and a future therapeutic target for aggressive PCa in African American men. Our findings may be useful for categorizing African American patients with a higher probability of recurrent disease and metastasis from those who are likely to remain metastasis-free.

Metastasis-associate protein 1 (MTA1) plays essential role in prostate cancer (PCa) progression and metastasis. We hypothesized that nuclear MTA1 overexpression in primary tumor tissues may provide meaningful information on prediction of poor prognosis, i.e. MTA1 may serve as a prognostic biomarker for aggressive PCa and a predictor of recurrent disease and metastasis. We used tissue microarrays and clinicopathological information of 301 patients (146 Caucasian Americans and 155 African Americans) who underwent prostatectomy in University of Mississippi Medical Center, Jackson, MS and in University of Iowa, Iowa City, IA. We evaluated MTA1 expression by immunohistochemistry with the emphasis on subcellular localization and total staining score, which accounted intensity and frequency. MTA1 was detected in both cytoplasm and nucleus, however exhibited different expression patterns in terms of subcellular localization depending on pathological category of PCa and metastasis. A significant statistical correlation (p=0.063) was observed between MTA1 nuclear staining and localized PCa compared to PIN, reaching more significance with the worst grade (Gleason >7) and metastatic lesions (p<0.006). When analyzed in terms of racial differences, the difference in MTA1 nuclear overexpression between patients with localized PCa was highly significant (p<0.001), with Caucasian Americans showing higher levels of MTA1. However, when stratified by Gleason score, there were substantial differences in MTA1 levels in low grade tumors (Gleason ≤ 7) compared to high grade tumors (Gleason>7) in African Americans and not in Caucasians, indicating that MTA1 may serve as an “ethnic” biomarker for aggressive disease in African Americans. Moreover, there was a tendency for higher MTA1 nuclear staining in recurrent compared to non-recurrent group (n=50), particularly in African Americans (2.3 times difference). In summary, our observation might have clinical relevance in discriminating subset of low grade Gleason≤7 African American patients with low MTA1 expression who will remain recurrent-free from the same subset that have high MTA1 levels indicating possibility to develop more aggressive disease and metastasis. Putting together results of the current study and our previous finding that MTA1 is downregulated by dietary stilbenes we emphasize new perspectives for PCa management in African American men. Citation Format: Steven J. Dias, Xinchaun Zhou, Marina Ivanovic, Michael P. Gailey, Swati Dhar, Zhi He, Alan Penman, Anait S. Levenson. Nuclear MTA1 overexpression is associated with aggressive prostate cancer and metastasis in African American men. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4. doi:10.1158/1538-7445.AM2013-4