Inactivation of AR and Notch-1 signaling by miR-34a attenuates prostate cancer aggressiveness

Prostate cancer (PCa) is the second leading cause of cancer related death in men in the United States, suggesting that novel molecular targets as well as the development of agents that could deregulate such targets would become newer therapeutic approach for the treatment of castrate resistant prostate cancer (CRPC) especially the metastatic CRPC (mCRPC). In search for novel targets, microRNAs (miRNAs) are becoming an emerging area because miRNAs function as regulators of gene expression in human cancers including PCa. Previous studies from our laboratory have shown that the expression of miR-34a is significantly down-regulated in human PCa specimens consistent with PCa cell lines with aggressive characteristics, and that the silencing of miR-34a expression was in part due to hypermethylation of its promoter. There are several genes that are direct targets of miR-34a, and in the current study we investigated the cellular consequence of miR-34a over-expression and under-expression in the regulation of androgen receptor (AR) and Notch-1 in PCa cells. We found that over-expression of miR-34a led to reduced expression of AR, PSA and Notch-1. We also found that over-expression of miR-34a significantly inhibited the growth of PCa cells. Moreover, over-expression of miR-34a resulted in decreased self-renewal capacity of PCa cells, and conversely inactivation of miR-34a led to increased self-renewal capacity, which is an indication of tumor cell aggressiveness. These findings suggest that the loss of miR-34a is directly linked with up-regulation of AR and Notch-1 both of which are highly expressed in PCa, and thus finding innovative approaches by which miR-34a expression could be up-regulated will have a huge impact on the treatment of PCa especially for the treatment of mCRPC.