Data from miRNA-34b Inhibits Prostate Cancer through Demethylation, Active Chromatin Modifications, and AKT Pathways

Abstract

<div>Abstract<p><b>Purpose:</b> miRNAs can act as oncomirs or tumor-suppressor miRs in cancer. This study was undertaken to investigate the status and role of miR-34b in prostate cancer.</p><p><b>Experimental Design:</b> Profiling of miR-34b was carried out in human prostate cancer cell lines and clinical samples by quantitative real-time PCR and <i>in situ</i> hybridization. Statistical analyses were done to assess diagnostic/prognostic potential. Biological significance was elucidated by carrying out a series of experiments <i>in vitro</i> and <i>in vivo</i>.</p><p><b>Results:</b> We report that miR-34b is silenced in human prostate cancer and the mechanism is through CpG hypermethylation. miR-34b directly targeted methyltransferases and deacetylases resulting in a positive feedback loop inducing partial demethylation and active chromatin modifications. miR-34b expression could predict overall and recurrence-free survival such that patients with high miR-34b levels had longer survival. Functionally, miR-34b inhibited cell proliferation, colony formation, migration/invasion, and triggered G<sub>0</sub>/G<sub>1</sub> cell-cycle arrest and apoptosis by directly targeting the Akt and its downstream proliferative genes. miR-34b caused a decline in the mesenchymal markers vimentin, ZO1, <i>N</i>-cadherin, and Snail with an increase in E-cadherin expression, thus inhibiting epithelial-to-mesenchymal transition. Finally we showed the antitumor effect of miR-34b <i>in vivo</i>. MiR-34b caused a dramatic decrease in tumor growth in nude mice compared with cont-miR.</p><p><b>Conclusion:</b> These findings offer new insight into the role of miR-34b in the inhibition of prostate cancer through demethylation, active chromatin modification, and Akt pathways and may provide a rationale for the development of new strategies targeting epigenetic regulation of miRNAs for the treatment of prostate cancer. <i>Clin Cancer Res; 19(1); 73–84. ©2012 AACR</i>.</p></div>