DESCRIPTION (provided by applicant): Alteration of chromatin modification plays a major role in tumorigenesis, disease progression and therapeutic resistance. The chromatin landscape is also altered in the case of resurgent androgen receptor activity that is thought to promote castration resistant prostate cancer (CPRC). We describe here an understudied transcription repression complex including two proteins, Unconventional prefoldin RBP5 interactor (URI) and Androgen Receptor Trapped clone 27 (ART-27) that modulate chromatin to impact AR and polymerase binding. We showed that ART-27 is excluded from the nucleus in recurrent prostate cancer and is critical for AR antagonist action. URI and ART-27 are stably bound to chromatin prior to androgen stimulation and depletion of URI results in diminished H3K9 tri-methylation and increased AR and polymerase recruitment on Nkx3.1 gene regulatory sequences. Recently, we have shown that URI interacts with a KAP1 protein- containing complex to regulate high copy number DNA repeats that comprise greater than 40% of the human genome and are a result of recently active retrotransposons. Expression of the endonuclease encoded by the LINE-1 retroelement is linked to formation of genes fusions, such as TMPRSS2/ERG and we present evidence that misregulation of the ART-27/URI complex results in increased retroelement expression, increased gene fusion and altered regulation of AR target genes in prostate cancer. Very little is known about the nuclear role of ART-27 and URI, much less the contribution of retroelement expression to cancer progression and/or generation of fusion gene products. Thus, our aims are to 1) Examine the impact of ART-27 ablation on prostate cell growth and in mouse models of prostate cancer 2) Determine the mechanism of ART-27 and URI- mediated gene and retroelement repression 3) Determine the AR dependence of retroelement expression in prostate cancer cells and the role of the ART-27/URI protein complex in TMPRSS2/ERG translocation.

PUBLIC HEALTH RELEVANCE: Treatment resistant prostate cancer is life threatening for thousands of individuals every year. Our studies will provide new insight into the mechanism of genomic instability driving aggressive prostate cancer.