Epigenetie alterations have been hypothesized to play important roles in carcinogenesis and tumor progression, including the development of CRPC. Work from several groups including our own demonstrates a continued critical role for the androgen receptor (AR) in CRPC. In addition, recent work from our lab defining the AR cistromes in a model of androgen-dependent prostate cancer and CRPC has shown that AR is recruited to distinct genomic sites in CRPC where it executes a distinct transcriptional program. These CRPC selective AR binding sites harbor epigenetie chromatin marks characteristic of active transcriptional enhancers and regulate a set of cell cycle regulatory genes including CDK1, CCNB1, CDC20 and UBE2C that are required for CRPC growth. These same genes are over-expressed in authentic cases of CRPC. EZH2, a SET domain histone methyltransferase known to play a role in gene silencing through H3K27 methylation is up-regulated in CRPC. In preliminary studies we have found that EZH2 can be recruited to the cis-regulatory elements of CRPC selective AR target genes such as CDK1 and UBE2C, forming a complex with AR in prostate cancer cells. Surprisingly, EZH2 directly up-regulates these AR targets in CRPC cells but not in androgen-dependent prostate cancer cells. In addition EZH2 is required for the growth of CRPC cells. Thus the overall hypothesis that will be tested in this study is that the epigenetie regulator EZH2 reprograms AR function in CRPC to stimulate the induction of a set of cell cycle regulatory genes required for the AR dependent growth of CRPC. |n Aim 1 we will analyze EZH2-dependent gene expression profiles and cistromes in CRPC cells;
in Aim 2 we will determine the mechanisms underlying the interaction between AR and EZH2 in modulating the specific subset of genes up-regulated in CRPC by AR;and in Aim 3 we will utilize the Biospecimen and Animal Models Core to profile gene expression, epigenetie chromatin modifications, EZH2 and AR cistromes and DNAse I hypersensitivity in xenograft models of CRPC in order to validate the findings from cell culture.
Understanding of the function of the androgen receptor (AR) in castration resistant prostate cancer (CRPC) will lead to improvements in therapy for this lethal form of the disease. Epigenetie reprogramming by EZH2 presents a potential novel mechanism of activation of AR function in CRPC and if validated a potential new therapeutic target.
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