Androgen receptor plays a significant role in prostate carcinogenesis and its overexpression and aberrant activation are considered to be the underlying cause for the development of castration-resistant tumors, which at present defy any effective treatment. As a transcriptional factor, androgen receptor is involved in the assembly of transcriptional complex including coactivators on the target genome site. One special class of coactivators are histone modifying enzymes and the best understood are histone acetylases. A newly emerging class is histone demethylase, which serves to remodel the chromatin surrounding the androgen receptor binding site. They are thus both transcriptional coactivator and epigenetic regulator. The present proposal is based on our identification of a new histone demethylase with all the hallmarks of a strong coactivator of androgen receptor and is overexpressed in prostate cancer. It enhances androgen response, accelerates cell cycle progression, and exhibits a substrate specificity different from the known histone demethylases. Intriguingly, it is regulated by growth factor and is phosphorylated by tyrosine kinases. The enzyme is cell cycle regulated but also regulates cell cycle. Based on these preliminary observations, we wish to elucidate its biochemical properties as a demetylation enzyme, its regulation as a signal transducer, and its biological effects as an androgen receptor coactivator. Its potential as a biomarker and/or a target for therapy will also be evaluated.
Increasing evidence suggests that over 90% of castration-resistant prostate cancers have evolved ways to aberrantly activate androgen receptor either due to androgen receptor mutations, amplification, increase of intracrine androgen, posttranslational modification of androgen receptor or association of deregulated coactivators. Thus, targeting aberrantly activated androgen receptor or its dysregulated coactivators is likely to be the most fruitful strategy to interfere with the development of hormone-refractory tumors. Strategy to interfere with ligand binding is one option, but it fails to target truncated androgen receptor. Targeting co-activators is another strategy, but most of the co-activators are not enzymes, which makes the development of small-molecule inhibitors more difficult. Our finding that histone demethylase, an enzyme, is a coactivator thus offers an ideal target for this intervention. If SAHA, an inhibitor for histone deacetylase and a clinically approved drug, is a pertinent example, this new histone demethylase could be an ideal enzyme-based target for prostate cancer. Their consistent overexpression in prostate cancer specimens shown in our preliminary data suggests it could also potentially be a good biomarker for aberrant activation of androgen receptor. The overall relevance of this proposal to prostate cancer includes : 1) It offers a new handle to understand the epigenetic regulation of androgen receptor activity and thus prostate cancer development. 2) It offers a potentially new biomarker for transformation and/or aberrant activation of androgen receptor in the prostate carcinogenesis, and 3) It offers a potentially new enzyme-based target for interfering with prostate carcinogenesis.
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