Function of androgen receptor trapped clone-27 in prostate cancer cells.

摘要

The Androgen Receptor (AR) directs androgen-regulated biological processes such as prostate development and prostate cancer progression, as well as resistance to antiandrogen therapy by regulating specific transcriptional programs. In the prostate, Androgen Receptor Trapped clone-27 (ART-27) is an epithelial cell-specific protein that binds and modulates the transcriptional activity of AR. ART-27 expression is upregulated during prostate development, and often downregulated in prostate cancer. Moreover, ART-27 overexpression suppresses proliferation of prostate cancer (LNCaP) cells, suggesting that in the prostate, ART-27 likely functions as a tumor suppressor via an unknown mechanism.;I have identified a cell type-specific mechanism governing the transcription of ART-27 that likely operates during prostate development. I also provide evidence suggesting that ART-27 functions as an AR corepressor in LNCaP cells -- a role that is consistent with its putative tumor suppressor function in the prostate -- by defining the impact of ART-27 loss on androgen-regulated transcription on a genome-wide scale. I have further established the functional relevance for ART-27 in antiandrogen response in LNCaP cells. My work also investigated the importance of the ART-27-binding proteins, Unconventional prefoldin Rpb5-interactor (URI) and S-phase Kinase-associated protein 2 (SKP2) in androgen-dependent transcription. Collectively, my findings demonstrate that ART-27, in concert with URI and/or SKP2, suppresses AR-mediated gene transcription and in turn androgen-dependent proliferation of prostate cells.