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

Abstract

SUMMARY The Polycomb group transcriptional repressor Bmi-1 is often up-regulated 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 beta-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.

MicroRNA-31 Is a Transcriptional Target of Histone Deacetylase Inhibitors and a Regulator of Cellular Senescence

“…Aberrant expression of BMI1 is associated with the bypass of senescence, increased proliferation, and oncogenic phenotypes such as increased migration, invasion, and metastasis of cancer cells (14,15,18,25,43). BMI1 is also known to promote CSC properties and therapy resistance in breast and prostate cancers (17,44). Hence, the therapeutic targeting of BMI1 can potentially help in the prevention, treatment, and recurrence of breast, prostate, and possibly other cancers.…”

Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages

“…The lineage relationship between basal and luminal cells has recently been under heavy debate. Although renal capsule or subcutaneous transplantation experiments support the traditional view that basal cells have the ability to regenerate the prostate gland by repopulating all prostate epithelial lineages [1][2][3][4] , evidence from the rescued explants of p63-null mice suggest that luminal cells can sustain a prostate structure independently of basal cells 5 . In addition, with transgenic reporter mice, a population of castration-resistant Nkx3.1-expressing luminal cells has been shown to be able to generate not only luminal cells but also other prostatic epithelial lineages 6 .…”

“…Generally, it is believed that basal cells are likely the cellular origin of prostate cancer 3,4,10,11 . However, it is also known that prostate cancer always displays a remarkable luminal phenotype including the amplification of luminal cells rather than basal cells and overproduction of luminal-derived prostate-specific protein (PSA) 12,13 .…”

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

“…14,18e24 Recently, increasing evidence has linked EMT to stem cell properties, indicating that the key molecules inducing EMT may also promote a stem or progenitor cellelike phenotype with capabilities of self-renewal and increased tumorigenicity. 25e27 PC stem-like cells express proteins such as Oct4, Sox2, Nanog, Nestin, CD133, CD44, 28,29 and BMI1, 30 of which BMI1 is a member of the polycombrepressive complex and a crucial suppressor of prosenescence mediated by p16 INK4a , p14 ARF , and p15 INK4b . 31e33 Twist1 has been recently shown to induce BMI1 expression through a direct binding to the BMI1 promoter, 34 thus linking stem-like properties of cancer cells to EMT.…”