Role of Polycomb Group Gene BMI1 in the Development of Prostate Cancer.

摘要

We proposed to investigate the role of BMI1 (a member of polycomb gene family) in human prostate cancer (CaP) development. Here, we present the work accomplished during the last 5 months (after submitting the 1st annual report of the project.) In 1st annual report we showed that BMI1 protein levels are highly elevated in human CaP patients and we investigated the mechanistic basis of the role of BMI1 in human CaP. We showed that BMI1- silenced CaP cells exhibit decreased proliferative and clonogenic potential. On the contrary, BMI1-overexpressing CaP cells exhibited the reverse. Based on the outcome of micro-array and PCR array analysis, we showed that silencing of BMI1 caused a decrease in the cyclin D1 (Wnt target) and Bcl-2 (Sonic Hedgehog-SHH target), however an increase in p16 was observed. Conversely, overexpression of BMI1 exhibited the reverse effects. In the current report we provide novel findings about the transcriptional activation of Bcl-2 in CaP cells. We provide evidence that BMI1 induces the Bcl-2 expression in CaP cells suggesting the involvement of other pathway too in the regulation of Bcl-2 transcriptional activation. Another important finding of our report is that we identified those Bcl-2 acts as a novel Wnt target in CaP cells. We found that BMI1 regulates (i) activity of TCF4 transcriptional factor and (ii) binding of TCF4 to the promoter region of anti-apoptotic BCL2 gene. Notably, an increased TCF4 occupancy on BCL2 gene was observed in prostatic tissues exhibiting high BMI1 levels. Using tumor cells other than CaP, we also showed that regulation of TCF4-mediated BCL2 by BMI1 is universal. It is noteworthy that forced expression of BMI1 was observed to drive normal cells to hyperproliferative mode. We show that targeting BMI1 improves the outcome of docetaxel therapy in animal models bearing chemoresistant prostatic tumors. Finally, by employing BlueGen/L Super computer modeling, we identified small molecule inhibitors of BMI1.