Prostate cancer is the most common non-skin malignancy in men and is responsible for more deathsthan any other cancer, except for lung cancer. According to the American Cancer Society (ACS), about218,890 new cases of prostate cancer were diagnosed in the United States during 2007 and about 1 man in 6will be diagnosed with prostate cancer during his lifetime. It is well established that androgen plays animportant role in promoting prostate cancer initiation/development. Therefore, it is essential to understand themechanism of androgen receptor (AR) target gene expression, which is at the center stage of prostate cancerresearch. Although our knowledge of the molecular mechanisms by which the AR regulates gene transcriptionand its possible link to prostate cancer is increasing, several interesting questions remain to be answered.Thus, the major hypothesis in this proposal is that ncRNA-dependent relocation of gene regulatory regionsbased on covalent modifications of specific histone mark "readers," such as Pc2, are critical components of theregulatory machinery underlying the transcriptional actions of nuclear receptors, including AR. Specifically, theproposed study aims to: 1) define non-histone methylation/demethylation of Pc2 as a novel molecular strategyresponsible for genome-wide AR transcriptional programs; 2) determine the androgen-induced relocation of ARtarget genes between PcG bodies and interchromatin granules and the potential involvement of ncRNAs; 3)investigate the role of ncRNAs in modulating androgen-dependent gene regulatory programs and theirpotential relevance for the prostate cancer development. The major novel aspect of this study is that ituncovers a new component of the regulatory machinery required for androgen-dependent gene regulatoryprograms by providing a biologically and clinically innovative mechanism by which AR-targeted genes areregulated, in part, by the dynamic ligand-dependent relocation from transcriptional repressive to permissivenuclear bodies involving the functional interplay between the non-histone Pc2 methylation events and theresultant specific ncRNA associations. Generally, this mechanism may serve to integrate actions oftranscription factor/co-regulators, non-histone protein methylation, and ncRNAs resident in distinct subnucleararchitectural structures to achieve coordinated activation for nuclear receptor target genes. The results fromthe proposed study may facilitate the development of novel prostate diagnosis and therapeutic strategies.
