The Polycomb group (PcG) gene BMI1 is required for the proliferation and 
self-renewal of normal and leukemic stem cells. Overexpression of Bmi1 oncogene 
causes neoplastic transformation of lymphocytes and plays essential role in 
pathogenesis of myeloid leukemia. Another PcG protein, Ezh2, was implicated in 
metastatic prostate and breast cancers, suggesting that PcG pathway activation 
is relevant for epithelial malignancies. Whether an oncogenic role of the BMI1 
and PcG pathway activation may be extended beyond the leukemia and may affect 
progression of solid tumors as well remains unknown. Here we demonstrate that 
activation of the BMI1 oncogene-associated PcG pathway plays an essential role 
in metastatic prostate cancer, thus mechanistically linking the pathogenesis of 
leukemia, self-renewal of stem cells, and prostate cancer metastasis. To 
characterize the functional status of the PcG pathway in metastatic prostate 
cancer, we utilized advanced cell- and whole animal-imaging technologies, gene 
and protein expression profiling, stable siRNA-gene targeting, and tissue 
microarray (TMA) analysis in relevant experimental and clinical settings. We 
demonstrate that in multiple experimental models of metastatic prostate cancer 
both BMI1 and Ezh2 genes are amplified and gene amplification is associated with 
increased expression of corresponding mRNAs and proteins. For the first time, we 
provide images of human prostate carcinoma metastasis precursor cells isolated 
from blood and shown to overexpress both BMI1 and Ezh2 oncoproteins. Consistent 
with the PcG pathway activation hypothesis, increased BMI1 and Ezh2 expression 
in metastatic cancer cells is associated with elevated levels of H2AubiK119 and 
H3metK27 histones. Quantitative immunofluorescence colocalization analysis and 
expression profiling experiments documented increased BMI1 and Ezh2 expression 
in clinical prostate carcinoma samples and demonstrated that high levels of BMI1 
and Ezh2 expression are associated with markedly increased likelihood of therapy 
failure and disease relapse after radical prostatectomy. Gene-silencing analysis 
reveals that activation of the PcG pathway is mechanistically linked with highly 
malignant behavior of human prostate carcinoma cells and is essential for in 
vivo growth and metastasis of human prostate cancer. We conclude that the 
results of experimental and clinical analyses indicate the important biological 
role of the PcG pathway activation in metastatic prostate cancer. Our work 
suggests that the PcG pathway activation is a common oncogenic event in 
pathogenesis of metastatic solid tumors and provides justification for 
development of small molecule inhibitors of the PcG chromatin silencing pathway 
as a novel therapeutic modality for treatment of metastatic prostate cancer.