Determinants of Receptor- and Tissue-Specific Actions in Androgen Signaling

Abstract

The physiological androgens testosterone and 5α-dihydrotestosterone regulate the development and maintenance of primary and secondary male sexual characteristics through binding to the androgen receptor (AR), a ligand-dependent transcription factor. In addition, a number of nonreproductive tissues of both genders are subject to androgen regulation. AR is also a central target in the treatment of prostate cancer. A large number of studies over the last decade have characterized many regulatory aspects of the AR pathway, such as androgen-dependent transcription programs, AR cistromes, and coregulatory proteins, mostly in cultured cells of prostate cancer origin. Moreover, recent work has revealed the presence of pioneer/licensing factors and chromatin modifications that are important to guide receptor recruitment onto appropriate chromatin loci in cell lines and in tissues under physiological conditions. Despite these advances, current knowledge related to the mechanisms responsible for receptor- and tissue-specific actions of androgens is still relatively limited. Here, we review topics that pertain to these specificity issues at different levels, both in cultured cells and tissues in vivo, with a particular emphasis on the nature of the steroid, the response element sequence, the AR cistromes, pioneer/licensing factors, and coregulatory proteins. We conclude that liganded AR and its DNA-response elements are required but are not sufficient for establishment of tissue-specific transcription programs in vivo, and that AR-selective actions over other steroid receptors rely on relaxed rather than increased stringency of cis-elements on chromatin.

Androgen receptor- and PIAS1-regulated gene programs in molecular apocrine breast cancer cells

“…Genome-wide analyses have revealed that, by and large, AR regulates transcription via AR-binding sites (ARBs) in distal enhancers instead of binding to promoter regions (Pihlajamaa et al, 2015;Tang et al, 2011). In addition to androgen response elements (AREs) in the ARBs, the region of AR chromatin occupancy encompasses cis-elements for other transcription factors (TFs), such as pioneer TFs GATA-binding protein 2 (GATA2) and forkhead box A1 (FOXA1), E twenty-six or E26 transformation-specific (ETS) TFs and homeodomain protein HOXB13 (Carroll et al, 2005;Sahu et al, 2011;Wu et al, 2014).…”

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Coregulators as mediators of mineralocorticoid receptor signalling diversity

“…Pascual-Le Tallec and coworkers (Pascual-Le Tallec et al 2003) reported promoter dependence for MR corepression by PIAS1, and Yang and coworkers (Yang et al 2014(Yang et al , 2015 reported gene-specific effects for GEMIN4, XRCC6, EEF1A1 and SSRP1. These differences may be mediated by other transcription factors including so-called pioneer/licensing factors such as FOXAI which have been extensively characterized for steroid receptors particularly the AR (Pihlajamaa et al 2015). Large-scale gene expression profiling and coactivator recruitment assays for novel progesterone receptor modulators have also found that regulation is highly gene specific despite a common coactivator recruitment profile for certain compounds (Berrodin et al 2009).…”

The role of the androgen receptor and hydroxysteroid 17β dehydrogenase in breast cancer : Impact on tamoxifen treatment

“…These binding sites are characterized by cofactors and by pioneering factors like AP-2, FoxA1 and GATA3. Pioneering factors are proteins which facilitate the binding of nuclear receptors to their targets by opening up the chromatin, without them the binding is greatly diminished (17,18). Further cofactors are recruited following ER binding.…”

“…Further cofactors are recruited following ER binding. ER binds to the estrogen response elements (ERE) located in promotors (18) or distal sites from where ER interacts with targets by chromatin looping (17). In the non-classical genomic pathway, phosphorylated ER can act independently of ligands, as a response to p38 MAPK, JNK or PI3K/AKT signaling.…”

“…It is believed that the sequence of the binding site in itself is only part of the requirement for specific binding, since cofactors and pioneering factors such as FoxA1 and GATA2 are pivotal in facilitating AR binding. The primary AR response occurs within seconds and peaks around a few hours (18).…”