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Steroid hormone receptors play diverse roles in many aspects of human physiology including cell division, apoptosis and homeostasis, tissue differentiation, sexual development and response to stress. These ligand-activated transcription factors require the functional activity of numerous chaperone and chaperone-associated proteins, collectively termed the foldosome, at the crucial step of ligand recognition and binding. Since the initial isolation of foldosome components and pioneering research by Pratt, Toft and colleagues we understand much regarding cytosolic receptor function. The classical view, that the role of foldosome components is restricted to the cytosol, has been modified over recent years by research highlighting additional roles of chaperone proteins in nuclear translocation and target gene expression. Further, dysregulation of chaperone activity and expression has been implicated in various cancers, including breast and prostate cancer. Consequently, the foldosome provides an attractive therapeutic target in steroid hormone receptor-driven malignancies. This review summarises current knowledge of how the foldosome impacts upon androgen receptor signalling, which is the key therapeutic target on prostate cancer, and how foldosome components may be used as biomarkers or therapeutic targets in this disease.

Prostate tumor growth initially depends on androgens, which act via the androgen receptor (AR). Despite androgen ablation therapy, tumors eventually progress to a castrate-resistant stage in which the AR remains active. The mechanisms are poorly understood but it may be that changes in levels or activity of AR coregulators affect trafficking and activation of the receptor. A key stage in AR signaling occurs in the cytoplasm, where unliganded receptor is associated with the heat shock protein (HSP)90 foldosome complex. p23, a key component of this complex, is best characterized as a cochaperone for HSP90 but also has HSP90-independent activity and has been reported as having differential effects on the activity of different steroid receptors. Here we report that p23 increases activity of the AR, and this appears to involve steps both in the cytoplasm (increasing ligand-binding capacity, possibly via direct interaction with AR) and the nucleus (enhancing AR occupancy at target promoters). We show, for the first time, that AR and p23 can interact, perhaps directly, when HSP90 is not present in the same complex. The effects of p23 on AR activity are at least partly HSP90 independent because a mutant form of p23, unable to bind HSP90, nevertheless increases AR activity. In human prostate tumors, nuclear p23 was higher in malignant prostate cells compared with benign/normal cells, supporting the utility of p23 as a therapeutic target in prostate cancer.

The Hairy/Enhancer-of-split-related with YRPW-like motif (HEY) family of proteins are transcriptional repressors and downstream effectors of Notch signaling. We previously reported that HEY1 and HEY2 selectively repress androgen receptor (AR) signaling in mammalian cell lines and have shown that in human tissue HEY1 is excluded from the nuclei in prostate cancer but not benign prostatic hyperplasia. We have now characterized a third member of this family, HEYL, which is a more potent repressor of AR activity. HEYL interacted with and repressed AR activation function-1 domain and competitively inhibited SRC1e activation of AR transcriptional activity. Using a cell line inducibly expressing exogenous HEYL, we showed that HEYL represses endogenous AR-regulated genes and reduces androgen-dependent prostate cancer cell growth. Using a trans-repression assay, we identified both trichostatin-sensitive and -insensitive domains within HEYL; however, analysis of endogenous AR target genes suggested that HEYL represses AR activity through histone deacetylase I/II-independent mechanisms. Immunohistochemical analyses of tissue indicated that, in a fashion similar to that previously reported for HEY1, HEYL is excluded from the nuclei in prostate cancer but not adjacent benign tissue. This suggests that nuclear exclusion of HEY proteins may be an important step in the progression of prostate cancer. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc., This work was supported by Cancer Research UK Grants C11509/A8570 and C11509/A12426 and Ministerio de Ciencia e Innovación Grants SAF2007-62642 and SAF2010-21013.

The androgen receptor (AR) is a ligand activated transcription factor and member of the steroid hormone receptor (SHR) subfamily of nuclear receptors. In the early stages of prostate carcinogenesis, tumour growth is dependent on androgens, and AR directly mediates these effects by modulating gene expression. During transcriptional regulation, the AR recruits numerous cofactors with acetylation-modifying enzymatic activity, the best studied include p300/CBP and the p160/SRC family of coactivators. It is known that recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) is key in fine-tuning responses to androgens and is thus likely to play a role in prostate cancer progression. Further, these proteins can also modify the AR itself. The functional consequences of AR acetylation, the role of modifying enzymes in relation to AR transcriptional response, and prostate cancer will be discussed.

The transcription factor PAX6 is essential for eye development and is found in several ocular cell types, including the corneal and limbal epithelia, where gene expression is maintained throughout life.1-4 Heterozygous deficiencies in PAX6 are characterized by iris hypoplasia, corneal epithelial fragility, persistent lens-corneal bridge (Peter's anomaly) and corneal opacity, with vascularization and inflammation termed aniridic keratopathy or aniridia-related keratopathy (ARK).5-8 Mouse Pax6+/− corneas are an excellent model of human ARK.4,6,9-11 The corneal epithelium is one of the most densely innervated tissues of the body and receives sensory nerve fibers that originate principally in the trigeminal ganglion.12-14 The nerve bundles enter the corneal periphery radially to form the perilimbal ring.15 Bundles of fibers project and extend through the corneal stroma, subdivide, penetrate the anterior limiting lamina, and innervate the corneal epithelium, forming a basal epithelial nerve plexus.13,14 The mechanisms that control corneal epithelial nerve growth are incompletely known, but wound-induced electric currents have been shown to direct nerve regeneration after epithelial wounding.16 Corneal nerves maintain a healthy cornea through the release of soluble trophic factors.17,18 Substance P (SP) is of particular importance; it acts synergistically with other growth factors, including nerve growth factor (NGF), to accelerate corneal epithelial cell migration and proliferation during healing and regeneration.18-27 Disruption of corneal innervation can cause degenerative conditions ranging from dry eye to neurotrophic keratitis.28 The symptoms accelerate cell loss leading to corneal epithelial thinning, increased epithelial permeability, and wound healing deficiency. Most neurotrophic keratitis results from herpetic viral infection; however, ocular surgery such as laser-assisted in situ keratomileusis (LASIK) and corneal transplants, even the use of contact lenses, can lead to damage of corneal nerves.28-31 We hypothesized that corneal epithelial degeneration in PAX6+/− humans and mice may be in part a type of neurotrophic keratitis.

Steroid hormones are a diverse class of structurally related molecules, derived from cholesterol, that include androgens, estrogens, progesterone and corticosteroids. They represent an important group of physiologically active signalling molecules that bind intracellular receptor proteins and regulate genes involved in developmental, reproductive and metabolic processes. The receptor proteins share structurally and functionally related ligand binding and DNA-binding domains, but possess distinct N-terminal domains (NTD) of unique length and amino acids sequence. The NTD contains sequences important for gene regulation, exhibit structure plasticity and are likely to contribute to the specificity of the steroid hormone/receptor response.

The androgen receptor (AR) is a widely expressed ligand-activated transcription factor which mediates androgen signalling by binding to androgen response elements (AREs) in normal tissue and prostate cancer (PCa). Within tumours, the amount of AR plays a crucial role in determining cell growth, resistance to therapy and progression to fatal castrate recurrent PCa in which prostate cells appear to become independent of androgenic steroids. Despite the pivotal role of the AR in male development and fertility and all stages of PCa development, the mechanisms governing AR expression remain poorly understood. In this work, we describe an active nonconsensus androgen response element (ARE) in the 5′ UTR of the human AR gene. The ARE represses transcription upon binding of activated AR, and this downregulation is relieved by disruption of the regulatory element through mutation. Also, multiple species comparison of the genomic region reveals that this ARE is specific to primates, leading to the conclusion that care must be exercised when elucidating the operation of the human AR in PCa based upon rodent promoter studies. Electronic supplementary material The online version of this article (doi:10.1007/s12672-014-0185-y) contains supplementary material, which is available to authorized users.

$('.header-date').hide();$('#titleAuthors').hide(); $('#abstractHeader').hide(); Greg N. Brooke 1 , 2 , Sue M. Powell 1 , Derek N. Lavery 1 , Jonathan Waxman 1 , Laki Buluwela 1 , Simak Ali 1 and Charlotte L. Bevan 1 1 Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College London, W12 0NN, UK. 2 School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, UK. Correspondence: Charlotte Bevan, Email: charlotte.bevan@imperial.ac.uk Keywords: androgen receptor, prostate cancer, anti-androgen, castrate resistant prostate cancer Received : September 05, 2013 Accepted : November 20, 2013 Published : January 21, 2014 ABSTRACT Prostate cancer growth is dependent upon the Androgen Receptor (AR) pathway, hence therapies for this disease often target this signalling axis. Such therapies are successful in the majority of patients but invariably fail after a median of 2 years and tumours progress to a castrate resistant stage (CRPC). Much evidence exists to suggest that the AR remains key to CRPC growth and hence remains a valid therapeutic target. Here we describe a novel method to inhibit AR activity, consisting of an interaction motif, that binds to the AR ligand-binding domain, fused to repression domains. These ‘engineered repressors’ are potent inhibitors of AR activity and prostate cancer cell growth and importantly inhibit the AR under circumstances in which conventional therapies would be predicted to fail, such as AR mutation and altered cofactor levels.