Regulators of Androgen Action Resource: a one-stop shop for the comprehensive study of androgen receptor action

Abstract

Androgen receptor (AR) is a ligand-activated transcription factor that is the main target for treatment of non-organ-confined prostate cancer (CaP). Failure of life-prolonging AR-targeting androgen deprivation therapy is due to flexibility in steroidogenic pathways that control intracrine androgen levels and variability in the AR transcriptional output. Androgen biosynthesis enzymes, androgen transporters and AR-associated coregulators are attractive novel CaP treatment targets. These proteins, however, are characterized by multiple transcript variants and isoforms, are subject to genomic alterations, and are differentially expressed among CaPs. Determining their therapeutic potential requires evaluation of extensive, diverse datasets that are dispersed over multiple databases, websites and literature reports. Mining and integrating these datasets are cumbersome, time-consuming tasks and provide only snapshots of relevant information. To overcome this impediment to effective, efficient study of AR and potential drug targets, we developed the Regulators of Androgen Action Resource (RAAR), a non-redundant, curated and user-friendly searchable web interface. RAAR centralizes information on gene function, clinical relevance, and resources for 55 genes that encode proteins involved in biosynthesis, metabolism and transport of androgens and for 274 AR-associated coregulator genes. Data in RAAR are organized in two levels: (i) Information pertaining to production of androgens is contained in a ‘pre-receptor level’ database, and coregulator gene information is provided in a ‘post-receptor level’ database, and (ii) an ‘other resources’ database contains links to additional databases that are complementary to and useful to pursue further the information provided in RAAR. For each of its 329 entries, RAAR provides access to more than 20 well-curated publicly available databases, and thus, access to thousands of data points. Hyperlinks provide direct access to gene-specific entries in the respective database(s). RAAR is a novel, freely available resource that provides fast, reliable and easy access to integrated information that is needed to develop alternative CaP therapies.Database URL: http://www.lerner.ccf.org/cancerbio/heemers/RAAR/search/

A comprehensive analysis of coregulator recruitment, androgen receptor function and gene expression in prostate cancer

“…Our design may have overlooked the contribution of lncRNAs ( Yang et al, 2013 ) to AR-dependent transcription. The 18 AR-associated coregulators studied here are only a small fraction of the >270 identified to date ( DePriest et al, 2016 ). Selection of coregulators for inclusion relied on knowledge of their differential protein expression in CaP.…”

Androgen Signaling in Prostate Cancer

“…Approximately 300 AR coregulators have now been identified (Heemers and Tindall 2007;DePriest et al 2016), which can coactivate or corepress AR transactivation and are increasingly recognized to do so in a target-gene-specific manner (Marshall et al 2003;Agoulnik and Weigel 2009;Ianculescu www.perspectivesinmedicine.org et al 2012). Within a large class of proteins with diverse cellular functions and characteristics, these coregulators commonly associate with AR to ensure effective transcription of target genes (Fig.…”

“…In addition, the use of innovative molecular screening approaches such as "Chem-seq"-in which biotin-tagged small molecules are captured by ChIP to link candidate compounds to regulated target genes-may increasingly reveal suitable agents to disrupt the transcriptional program of prostate cancer. Overall, efforts to elucidate key AR coregulators have shown an impressive number of potentially actionable proteins involved in the intricate, selective, and dynamic interplay with AR to promote AR signaling (DePriest et al 2016).…”

Seed-Mediated Rna Interference of Androgen Signaling and Survival Networks Induces Cell Death in Prostate Cancer Cells

“…The number of Hallmark Androgen Response genes within the leading edge for each shRNA are indicated in the table, and the 19 genes located in the leading edge for all shRNAs are listed. ( B ) –log10 p-value for enrichment of AR coregulatory genes (DePriest et al, 2016) and LNCaP essential genes (Fei et al, 2017) among significantly downregulated genes by each shRNA relative to shScramble expressing LNCaP cells. –log10 p-values are based on hypergeometric distribution.…”

“…Critical to AR-mediated signaling is the recruitment of AR coregulators, which modulate its transcriptional response. We therefore examined the effect of the three TMEFF2 and the L3 targeted shRNAs on AR-coregulatory gene expression and determined that an AR-coregulatory gene set (n=274) (DePriest et al, 2016) was significantly enriched among genes downregulated by each of the 4 shRNAs (Figure 3B). Moreover, since cell viability was also affected in non-PCa cell lines (HEK293-LX) which are not dependent on AR signaling, we analyzed the effect of these 4 shRNAs on expression of essential genes.…”