miRNA-128 Suppresses Prostate Cancer by Inhibiting BMI-1 to Inhibit Tumor-Initiating Cells

MicroRNA-128 (miR-128) is reduced in prostate cancer (PCa) relative to normal/benign prostate tissues but causal roles are obscure. Here we show that exogenously introduced miR-128 suppresses tumor regeneration in multiple PCa xenograft models. Cancer stem-like cell (CSC) associated properties were blocked, including holoclone and sphere formation as well as clonogenic survival. Using a miR-128 sensor to distinguish cells on the basis of miR-128 expression, we found that miR-128-lo cells possessed higher clonal, clonogenic and tumorigenic activities than miR-128-hi cells. miR-128 targets the stem cell regulatory factors BMI-1, NANOG, and TGFBR1, the expression of which we found to vary inversely with miR-128 expression in PCa stem/progenitor cell populations. In particular, we defined BMI-1 as a direct and functionally relevant target of miR-128 in PCa cells, where these genes were reciprocally expressed and exhibited opposing biological functions. Our results define a tumor suppressor function for miR-128 in PCa by limiting CSC properties mediated by BMI-1 and other central stem cell regulators, with potential implications for PCa gene therapy.