The Role of Polycomb Group Gene BMI1 in the Development of Prostate Cancer
Final rept. 1 Sep 2008-6 Dec 2013
MINNESOTA UNIV MINNEAPOLIS
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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 final phase of the project. During the 1st phase of study we established the relevance of BMI1 in the growth and proliferation of normal and malignant prostate tumor CaP cells. In the second phase 2nd annual report, we investigated the mechanistic basis of the role of BMI1 in human CaP and established the proof of principle for BMI1 as a relevant target for CaP therapy. As provided in the 2nd annual report, we showed the data generated from studies where we employed relevant cell-based models, gene modulation techniques such as micro-array and PCR array and animal models. These studies showed that BMI1 sustains the proliferation of chemoresistant CaP cells during and after chemotherapy by regulating the expression and activity of cyclin D1 Wnt target and Bcl-2 Sonic Hedgehog-SHH target. The novel finding in presented in the 2nd annual report was that regulation of Bcl-2 expression by BMI1 is independent of SHH activity in CaP cells. We showed that BMI1 regulates BCl2 by inducing the transcriptional activity of TCF4- transcriptional factor. Using cell-culture models and human prostatic tissues we showed that BMI1 regulates the binding of TCF4 on the promoter region of BCL2 gene. In the final report, we show that Cyclopamine SHH inhibitor which is known to reduce Bcl2, fails to inhibit the growth of chemoresistant CaP cells. However, targeting of BMI1 sensitizes such chemoresistant CaP cells to Cyclopamine SHH inhibitor therapy. We suggested that targeting of BMI1 is an ideal strategy to sensitize hard-to-treat CaP cells for chemotherapies. We show that targeting of BMI1 by gene-silencing improved the outcome of Docetaxel targets cell division and Sulindac Wnt-signaling inhibitor therapies in animal models bearing prostatic tumors.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research