The Role of HOX Proteins in Androgen-Independent Prostate Cancer
Annual summary rept. 30 Oct 2005-29 Oct 2006
COLORADO UNIV HEALTH SCIENCES CENTER AURORA CO
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Our preliminary data demonstrated that HOXC8 and HOXC6 overexpression inhibits androgen receptor AR-mediated signaling in human prostate cancer PCa cells. Based on these findings, coupled together with previous reports demonstrating that homeodomain-containing proteins interact with and inhibit the histone-acetyltransferase HAT activity of the steroid receptor coactivators CBP and p3001, we hypothesized that HOXC8 inhibits AR-mediated signaling through inhibition of CBPp300 HAT activity. In support of this hypothesis, we have recently shown that increased expression of CBP relieves HOXC8 induced inhibition of AR-mediated transcription in a dose dependent manner. Further, we have demonstrated by chromatin immunoprecipitation that hormone-induced histone acetylation at the androgen-responsive MMTV promoter in inhibited upon overexpression of HOXC8. We have created a series of PCa cell lines LNCaP, DU-145, PC-3-AR and ALVA-31 stably overexpressing HOXC8. We wanted to demonstrate that HOXC8 inhibition of AR-mediated signaling is upheld in cells stably overexpressing HOXC8, not just in transient experiments. We have demonstrated that PSA induction is inhibited in LNCaP-HOXC8 when compared with LNCaP empty vector control cells. We have also performed various tumorigenicity assays in these HOXC8 overexpressing cells, such as cell proliferation, migration, invasion and anchorage independent growth. However thus far we have been unable to detect any significant difference between the HOXC8 overexpressing cell lines and control cell lines in these experiments. Because HOXC8 overexpression may be involved in early tumorigenesis, we believe that it will be important to perform similar tumorigenicity assays in cells lines derived from non-transformed normal prostate epithelial cells. We have therefore recently created cell lines stably overexpressing HOXC8 using RWPE-I and PWR-IE prostate epithelial derived cell lines.
- Medicine and Medical Research