Mechanistic Roles of Long mcRNA-regulated Gene Transcription in Prostate Cancer

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Project Summary Prostate cancer is the most common non-skin malignancy in men and is responsible for more deaths than any other cancer, except for lung cancer. According to the American Cancer Society (ACS), about 218,890 new cases of prostate cancer were diagnosed in the United States during 2007 and about 1 man in 6 will be diagnosed with prostate cancer during his lifetime. It is well established that androgen plays an important role in promoting prostate cancer initiation/development. Therefore, it is essential to understand the mechanism of androgen receptor (AR) target gene expression, which is at the center stage of prostate cancer research. Although our knowledge of the molecular mechanisms by which the AR regulates gene transcription and 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 regions based on covalent modifications of specific histone mark "readers," such as Pc2, are critical components of the regulatory machinery underlying the transcriptional actions of nuclear receptors, including AR. Specifically, the proposed study aims to: 1) define non-histone methylation/demethylation of Pc2 as a novel molecular strategy responsible for genome-wide AR transcriptional programs; 2) determine the androgen-induced relocation of AR target 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 their potential relevance for the prostate cancer development. The major novel aspect of this study is that it uncovers a new component of the regulatory machinery required for androgen-dependent gene regulatory programs by providing a biologically and clinically innovative mechanism by which AR-targeted genes are regulated, in part, by the dynamic ligand-dependent relocation from transcriptional repressive to permissive nuclear bodies involving the functional interplay between the non-histone Pc2 methylation events and the resultant specific ncRNA associations. Generally, this mechanism may serve to integrate actions of transcription factor/co-regulators, non-histone protein methylation, and ncRNAs resident in distinct subnuclear architectural structures to achieve coordinated activation for nuclear receptor target genes. The results from the proposed study may facilitate the development of novel prostate diagnosis and therapeutic strategies.