Bmi-1 Is a Crucial Regulator of Prostate Stem Cell Self-Renewal and Malignant Transformation

SummaryThe Polycomb group transcriptional repressor Bmi-1 is often upregulated in prostate cancer, but its functional roles in prostate stem cell maintenance and prostate cancer are unclear. Loss- and gain-of-function analysis in a prostate sphere assay indicates that Bmi-1 expression is required for self-renewal activity and maintenance of p63+ stem cells. Loss of Bmi-1 blocks the self-renewal activity induced by heightened β-catenin signaling, suggesting that Bmi-1 is required for full activity of another self-renewal pathway. In vivo, Bmi-1 expression is necessary for normal prostate tubule regeneration. Altered self-renewal and proliferation through Bmi-1 modulation diminishes the susceptibility of prostate cells to transformation. In an in vivo prostate regeneration system, Bmi-1 inhibition protects prostate cells from FGF10-driven hyperplasia and slows the growth of aggressive Pten-deletion-induced prostate cancer. We conclude that Bmi-1 is a crucial regulator of self-renewal in adult prostate cells and plays important roles in prostate cancer initiation and progression.

► Bmi-1 regulates prostate stem cell maintenance and self-renewal in a sphere assay ► Bmi-1 loss reverses heightened self-renewal activity induced by β-catenin signaling ► Inhibition of Bmi-1 protects prostate cells from growth factor-induced hyperplasia ► Loss of Bmi-1 attenuates the formation of Pten-deletion-mediated prostate carcinoma