Aberrant Chromatin Modification as a Mechanism of Prostate Cancer Progression
Final rept. 1 Jun 2001-30 Nov 2004
CALIFORNIA UNIV DAVIS
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Prostate cancer almost inevitably progresses from hormone-dependent to hormone-independent state. However, the underlying mechanism is still unclear. The purpose of this study is to test the hypothesis that aberrant chromatin modification plays a critical role in prostate cancer progression. We proposed to analyze histone modifications on AR target genes such as PSA and identify the responsible enzymatic activities in prostate cancer cells. During the entire project time, we have made several major findings. First, we found that, in androgen-dependent cells, the level of histone acetylation at PSA gene is regulated by androgen and anti-androgen, regulatory DNA elements and promoter context. Secondly, we found that, in androgen-independent cells, histones are hyperacetylated without hormone stimulation, and AR and the coactivators containing histone acetylase HAT activities are recruited in an androgen-independent manner. Thirdly, we found that depletion of the HAT coactivator ACTR effectively blocks both androgen-dependent and -independent prostate cancer cell proliferation. Together, these results suggest that HAT proteins play an important role in the progression to hormone-refractory state. Interestingly, we also found that, in androgen-independent cells, AR and the coactivator ACTR controls cancer cell proliferation through distinct mechanisms. The findings support the idea that targeting HAT proteins such as ACTR can be an effective way to stop prostate cancer progression to androgen independence and the growth of hormone-refractory prostate cancer.
- Anatomy and Physiology
- Medicine and Medical Research