This review will provide a description of recent efforts in our laboratory contributing to a general goal of identifying critical determinants of prostate cancer growth in both androgen-dependent and -independent contexts. Important outcomes to date have indicated that the sustained activation of AR transcriptional activity in castration-resistant prostate cancer (CRPC) cells results in a gene expression profile separate from the androgen-responsive profile of androgen-dependent prostate cancer (ADPC) cells. Contributing to this reprogramming is enhanced FoxA1 recruitment of AR to G2/M phase target gene loci and the enhanced chromatin looping of CRPC-specific gene regulatory elements facilitated by PI3K/Akt-phosphorylated MED1. We have also observed a role for FoxA1 beyond AR signaling in driving G1/S phase cell cycle progression that relies on interactions with novel collaborators MYBL2 and CREB1. Finally, we describe an in-depth mechanism of GATA2-mediated androgen-responsive gene expression in both ADPC and CRPC cells. Altogether these efforts provide evidence to support the development of novel prostate cancer therapeutics that address downstream targets of AR activity as well as AR-independent drivers of disease-relevant transcription programs. 1. Introduction The androgen receptor (AR), a member of the steroid receptor superfamily [1], is a classic example of a ligand-inducible transcription factor whose activity is tightly linked to numerous physiological processes and disease states. Within the various mammalian tissues expressing AR, its essential role in organ development and function has been demonstrated, which ranges from contributions to spermatogenesis, sexual behavior, and skeletal maintenance [2]. Mechanistically, induction of AR activity relies upon binding to male hormones, androgens (e.g., testosterone or the more potent 5α-dihydrotestosterone [DHT]), resulting in release of AR from stabilizing interactions with cytoplasmic heat shock proteins (HSPs) [3]. Homodimerization, activation by posttranslational modification, and nuclear translocation of ligand-bound AR is then essential for its established role in determining tissue-, cell type-, and disease stage-specific gene expression patterns [3]. Within the nucleus, AR binds genomic regions enriched with its cognate DNA-binding motif, or androgen response element (ARE), consisting classically of the 15-base pair sequence 5′-AGAACAnnnTGTTCT-3′ and providing a degree of specificity to global AR distribution within regulatory elements of androgen responsive genes [4]. These regulatory
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