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Molecular Endocrinology, doi:10.1210/me.2007-0223
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Molecular Endocrinology 21 (12): 2855-2863
Copyright © 2007 by The Endocrine Society

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Androgen Receptor Structural and Functional Elements: Role and Regulation in Prostate Cancer

Scott M. Dehm and Donald J. Tindall

Departments of Urology and Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Donald J. Tindall, Departments of Urology and Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, Minnesota 55905. E-mail: tindall.donald{at}mayo.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 AR AND PROSTATE CANCER
 AR STRUCTURAL AND FUNCTIONAL...
 STRUCTURE AND FUNCTION OF...
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The androgen receptor (AR) is a nuclear receptor transcription factor that mediates the cellular actions of androgens, the male sex steroids. Androgen-dependent tissues, such as the prostate, rely on androgen action for their development as well as their maintenance in adulthood. This requirement is exploited during systemic therapy of prostate cancer, which is initially an androgen-dependent disease. Indeed, androgen ablation, which prevents the production or blocks the action of androgens, inhibits prostate cancer growth. Invariably, the disease recurs with a phenotype resistant to further hormonal manipulations. However, this so-called androgen depletion-independent prostate cancer remains dependent on a functional AR for growth. Many studies have focused on the mechanistic and structural basis of AR activation with the important goal of understanding how the AR is activated at this stage of the disease. In this review, we summarize how these studies have revealed important functional domains in the AR protein and have provided initial clues to their role in prostate cancer development and progression. A comprehensive understanding of the role and functional relationships between these AR domains could lead to the development of novel AR-directed therapies for prostate cancer.


   INTRODUCTION
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 ABSTRACT
 INTRODUCTION
AR AND PROSTATE CANCER
 AR STRUCTURAL AND FUNCTIONAL...
 STRUCTURE AND FUNCTION OF...
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 SUMMARY
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ANDROGENS, THE MALE sex steroids, are responsible for male sexual differentiation and development, as well as the maintenance and support of sexual tissues in the adult. Moreover, androgens are important for the development and progression of age-associated pathologies in men, including benign prostatic hyperplasia and prostate cancer (PCa). Androgen action is exerted through the androgen receptor (AR), a 110-kDa member of the steroid receptor family of transcription factors. Testosterone and dihydrotestosterone (DHT) are the physiological ligands for the AR. In prostate tissue, DHT is the primary ligand for the AR and is synthesized from testosterone by 5{alpha}-reductase enzymes. The classical model for AR subcellular dynamics, built largely on initial studies with the glucocorticoid receptor (GR), posits that unliganded AR is sequestered in the cytoplasm in a complex with members of the heat shock protein family of chaperones, and high-molecular weight immunophilins. Indeed, in normal prostate tissue and most PCa cell lines and xenografts, the AR is predominantly cytoplasmic under castrate conditions (reviewed in Ref. 1). The chaperone complex serves to induce a high-affinity conformation in the AR that is competent for ligand binding. Once bound to ligand, there is a change in the composition and conformation of the AR-chaperone complex, which exposes the bipartite AR nuclear localization signal, thus allowing translocation of AR to the nucleus.

Agonist-bound AR is highly mobile in the nucleus and engages with androgen response elements (AREs) in the promoter and enhancer regions of genes critical for the growth and survival of normal and cancerous prostate cells. The prototype AR-regulated gene, PSA, encodes prostate-specific antigen, a secreted serine protease, which is a major component of seminal fluid and an important biomarker for PCa development and progression. The mechanisms of AR-mediated transcription of the PSA gene have been studied extensively and have revealed that ARE-bound AR recruits a plethora of coregulatory proteins, which play important roles in the initiation of transcription, as well as the fine-tuning of overall transcriptional output (2, 3). Large-scale gene expression profiling studies have indicated that approximately 1.5–4.3% of genes expressed in PCa cells are directly or indirectly regulated by androgens (reviewed in Ref. 4). Ultimately, these AR-regulated genes have a profound impact on diverse cellular processes.

It is important to note that the AR may also mediate important cellular functions in the cytoplasm, independent of its role as a transcription factor (reviewed in Ref. 5). For example, the AR has been shown to participate in rapid signaling cascades, primarily through direct association with the c-Src tyrosine kinase. This nongenomic or nongenotropic mode of signaling, which activates the Raf-1/ERK pathway, has been shown to be intact in cell types of various origin, including PCa cells (6). Thus, a full appreciation of AR activity must take into account both genomic and nongenomic mechanisms. Considering the essential roles of the AR axis in normal and cancerous prostate tissue, a precise understanding of the mechanisms of AR regulation is of utmost importance. In this review, we will summarize the role of AR structural and functional elements in the overall regulation of AR activity and assess their contributions and significance to the development, progression, and treatment of PCa.


   AR AND PROSTATE CANCER
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 INTRODUCTION
 AR AND PROSTATE CANCER
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PCa is the most common male cancer and second leading cause of male cancer deaths in North America and other industrialized countries (7). The role of AR in PCa development and progression has been recently reviewed (8, 9, 10, 11, 12, 13). A role for the AR in the pathogenesis of PCa was first established by the pioneering work of Charles Huggins and Clarence Hodges (14) in 1941, which described that bilateral orchiectomy, or administration of the estrogen, diethylstilbestrol, were effective treatments for metastatic disease. Since this seminal work, for which Huggins was awarded the Nobel Prize in 1966, androgen ablation has been the mainstay systemic treatment for locally advanced or metastatic PCa, or disease that has relapsed after surgery. Currently, androgen ablation is most commonly achieved through administration of GnRH agonists such as leuprolide and/or AR antagonists such as bicalutamide (15). The importance of the AR in the pathogenesis of PCa has also been exploited for detection of the disease. For example, in the early 1990s, serum-based detection of PSA, an AR-regulated gene, was established as a useful approach to screening for PCa. Currently, serum PSA is used to monitor the success of radical prostatectomy or radiation therapy, local or distant disease recurrence after these treatments, response to androgen ablation, and emergence of a disease phenotype that is referred to as androgen-independent, androgen-refractory, or androgen depletion-independent (ADI) PCa (16). ADI PCa is a fatal manifestation of the disease that is resistant to further hormonal manipulations as well as other known treatments. Thus, significant efforts have been focused on understanding the molecular biology of this stage of the disease.

Data from clinical and experimental model systems point to the AR maintaining its status as a lynchpin for the growth and survival of ADI PCa cells. Foremost, the majority of ADI prostate cancers retain high levels of AR expression (17). Moreover, the PSA gene continues to be expressed at this stage of the disease (17). In vivo digital imaging of PSA promoter activity has shown that androgen-dependent PCa xenografts display a rapid but transient loss of AR function upon castration (18). After progression to an ADI stage, both AR DNA binding and resultant PSA promoter activity were fully restored in these xenografts (18). A direct role for AR in ADI PCa cells has also been demonstrated through AR-targeting experiments, which have employed diverse reagents such as ribozymes, antisense oligonucleotides, and small-interference RNA to inhibit AR expression. Invariably, these experiments have shown that targeted AR inhibition decreases PSA expression and cell proliferation in various cell-based models of androgen-refractory PCa (19, 20, 21, 22). Together, these studies provide compelling evidence that ADI PCa remains AR dependent.

If ADI PCa remains AR dependent, how is the AR activated at this stage of the disease? Numerous mechanisms have been described and are reviewed in detail elsewhere (23, 24, 25, 26). Briefly, aberrant AR activation can be achieved through ligand-independent mechanisms, sensitization to castrate levels of androgens, or agonist activity of alternative steroids or even antiandrogens. Mechanistically, these aberrant AR responses have been shown to result from AR mutation, overexpression, posttranslational modification, altered expression of AR-associated coregulatory proteins, or signal transduction pathways that enhance association of AR with coactivators or reduce association of AR with corepressors. As an alternative to this hypothesis of aberrant AR activation, analysis of androgen levels in recurrent PCa specimens has demonstrated that DHT levels, although decreased in serum as a result of androgen ablation, persist in PCa tissue at levels sufficient to elicit AR activation (27, 28). Therefore, it is possible that AR activity in ADI PCa could be achieved through traditional mechanisms in the presence of relatively high local concentrations of androgens. Mechanistically, this could result from increased local synthesis of testosterone from adrenal androgens (29) or decreased DHT catabolism in PCa cells (30).


   AR STRUCTURAL AND FUNCTIONAL ELEMENTS
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If AR signaling continues to regulate the growth and survival of ADI PCa cells, then a complete understanding of AR structure and function may lead to novel strategies that inhibit AR activity at this stage of the disease. The AR shares an overall modular organization similar to other steroid receptors (Fig. 1Go), having an N-terminal domain (NTD) harboring AR transcriptional activation function (AF)-1, a central DNA binding domain (DBD), a short hinge region, and a COOH-terminal domain (CTD), which contains both the AR ligand-binding domain (LBD) and AF-2 coactivator binding surface (31). The three-dimensional structures of peptides representing the LBD and AF-2 folds of the AR have been determined by x-ray crystallography, as has the three-dimensional structure of a peptide representing the AR DBD (32, 33, 34, 35, 36). The AR NTD, conversely, is unstructured in solution and thus has been recalcitrant to structural determination. Nevertheless, several critical functional domains have been described and characterized within the AR NTD. Posttranslational modifications of the AR, including phosphorylation, acetylation, ubiquitylation, and SUMOylation, add additional layers of regulation and are likely to influence the structure and function of these domains (37). In the following sections, we will summarize the current state of knowledge surrounding the structure and function of the AR protein.


Figure 1
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  		Fig. 1. Schematic of an AR Dimer Bound to an ARE

The modular domain organization of the AR is indicated. From N to C terminus, the AR is composed of an N-terminal transcriptional AF-1 domain, a zinc-finger DBD, a short hinge (h) region, and a C-terminal ligand-binding/AF-2 domain. Functional elements indicated along the length of the AF-1 domain are detailed and defined in the text. C, C terminus; N, N terminus.

 

   STRUCTURE AND FUNCTION OF THE AR CTD
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All steroid receptor CTDs perform a similar mechanistic function of binding their cognate ligand within a central LBD cavity, which induces formation of the AF-2 coactivator binding surface (Fig. 2Go). The role of the AR CTD is of particular importance for PCa, because the AR CTD is the foremost target of current androgen ablation therapies. For example, castration prevents binding of ligand to the LBD. This prevents both AR nuclear translocation and exposure of AF-2. Antiandrogens such as bicalutamide bind the LBD, block the activity of AF-2 (4), and cause AR to recruit corepressor molecules such as nuclear receptor corepressor (NCoR), Sin3, and MBD3 to the promoters of AR-regulated genes (2, 38, 39). Overall, these strategies prevent AR activity, thus inhibiting the growth and survival of androgen-dependent PCa cells. Understanding the structural basis of AR inhibition could be important for the design of more potent AR-targeted compounds that could serve as better long-term agents for PCa therapy.


Figure 2
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  		Fig. 2. Structure of the AR CTD Bound to the Synthetic Androgen, R1881, and a TIF2-Derived LxxLL Peptide

This figure was generated from coordinates deposited in the Protein Data Bank (2A06.pdb) and the MBT Protein Workshop application available from the Research Collaboratory for Structural Bioinformatics (85 ). Charge clamp residues K720 and E897 are shown for orientation purposes. H1, Helix 1.

 
The three-dimensional structure of many nuclear receptor CTDs have been solved by x-ray crystallography, revealing highly similar globular domains made up of 12 {alpha}-helices, which organize as three antiparallel helical sheets (reviewed in Ref. 40). The crystal structure of the human AR LBD bound to the synthetic androgen R1881 was first reported in 2000, revealing that the AR also forms a highly similar structure (32). However, the prototype globular {alpha}-helical sandwich organization is composed of 11 {alpha}-helices for the AR, as opposed to its family members’ 12, due to the absence of helix 2. Nevertheless, these helices are numbered 1–12, with helix 2 omitted to reflect the overall positional identity of these CTD helices in relation to other steroid receptor family members. A total of 18 amino acid residues, situated within each of the 11 AR LBD helices, are responsible for direct interactions with the ligand, with helix 12 functioning as a flexible lid to stabilize the ligand within the LBD cavity. Whereas most of these interactions are hydrophobic, the androgen O-3 hydrogen bonds with AR amino acids Q711, M745, and R752, and the 17β-OH hydrogen bonds with AR amino acids N705 and T877. Structures of both wild-type and mutant forms of rat and human AR LBDs in complex with a diverse list of agonists and antagonists have been described, including the natural AR ligand, DHT (33, 41, 42, 43, 44). These efforts have provided important glimpses into the structural basis of AR activation but have also begun to address issues important for PCa such as the structural basis of AR antagonism and AR ligand promiscuity.

To date, a structure of the wild-type AR LBD bound to antagonist has not been reported, owing to the instability of the AR LBD-antagonist complex (42). However, structures for W741L mutant AR LBD-bicalutamide and T877A mutant AR LBD-cyproterone acetate complexes have been solved (42, 44). The AR W741L mutation, which causes aberrant AR activation in response to bicalutamide, was first described after combined androgen deprivation and bicalutamide treatment of the LNCaP PCa cell line (45). The basis of aberrant activation of W741L AR likely stems from the observation that the LBD conformations of DHT-bound AR and bicalutamide-bound W741L AR are very similar (42). The AR T877A mutation has historically been of great interest, because it is found in the LNCaP cell line as well as cases of advanced PCa (46). This mutant thus serves as the prototype for altered AR ligand specificity caused by AR mutations in PCa. Structurally, the T877A mutation accommodates larger atoms at position 17 of the steroid D-ring (33, 44). At the functional level, this can allow aberrant AR activation in response to hydroxyflutamide, cyproterone acetate, and alternative steroids. Importantly, the T877A mutant AR has been shown to provide a selective growth and survival advantage in a cell-based model of PCa progression (47). Despite these mechanistic examples of how mutations in the AR LBD could lead to a therapy-resistant phenotype, the rate of AR mutation in ADI PCa is only approximately 10% (48).

Binding of ligand to the AR LBD causes a significant positional change in helix 12, as well as an overall conformational change in the AR CTD, which induces formation of the AF-2 coactivator binding surface (Fig. 2Go). The AF-2 surface is a hydrophobic groove flanked by concentrated regions of positive and negative charge. Similar to other nuclear receptors, the AF-2 surface serves as a docking site for LxxLL motifs present in prototype nuclear receptor coactivators and corepressors. Indeed, the crystal structures of liganded AR in complex with LxxLL-containing peptides derived from the AR coactivators SRC-2, SRC-3, and ARA70 have been described (34, 35). These crystal structures have revealed that K720 in helix 3 and E897 in helix 12 function as charge-clamp residues, which stabilize the LxxLL/AF-2 interaction (Fig. 2Go). Before elucidation of the AR LBD crystal structure it was apparent from sequence alignment that K720 and E897 were structurally and functionally homologous to charge clamp residues in other nuclear receptors. However, despite these findings, the relative role of AR AF-2 in coactivator recruitment has been unclear. For example, compared with LBD fragments derived from the GRs and estrogen receptors, the AR LBD displays very weak or even undetectable ligand-dependent transcriptional activity unless stimulated by p160 coactivators such as steroid receptor coactivator (SRC)-1 or SRC-2 [also referred to as transcriptional intermediary factor (TIF)2/GR-interacting protein 1 (49, 50, 51)]. This is in stark contrast to the potent inherent transcriptional activity of an isolated AR NTD fragment (51, 52, 53, 54, 55).

These observations have suggested that another important role may exist for AR AF-2. For example, in addition to serving as a docking site for coactivators, AR AF-2 is able to mediate interaction with the AR NTD in an intramolecular fashion (56). Biochemical evidence has demonstrated that this N/C interaction is mediated by direct binding of FxxLF and/or WxxLF motifs in the AR NTD with the AR AF-2 coactivator binding surface (57). The crystal structures of FxxLF- and WxxLF-containing peptides engaged with the AF-2 surface of ligand-bound AR have been described and have revealed a similar overall mode of binding to AF-2 as coactivator-derived LxxLL peptides (34, 35). Importantly, the AR AF-2 domain displays a higher affinity for NTD-derived FxxLF-containing peptides than coactivator-derived LxxLL-containing peptides, suggesting that N/C interaction, rather than direct transcriptional activation, may be the primary role for AF-2. From a functional standpoint, the N/C interaction is critical for the AR to bind a chromatin-integrated mouse mammary tumor virus promoter, but not a nonintegrated reporter (58). Moreover, AF-2 preferentially binds the NTD when the AR is mobile, but preferentially binds coregulators when the AR engages with DNA (59). Therefore, these findings suggest that N/C interaction may block inappropriate coregulator interaction until the AR is engaged with AREs in the promoter and enhancer regions of target genes. After AR is bound to DNA, the AF-2 cleft may be more amenable to coregulator binding, which would enhance the transcriptional activity of the AR.


   STRUCTURE AND FUNCTION OF THE AR DNA-BINDING AND HINGE DOMAINS
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The AR DBD/hinge region plays important roles in mediating AR nuclear localization, receptor dimerization, and DNA binding. Hormone receptor DBDs are highly conserved, consisting of two zinc-fingers and a loosely structured carboxy-terminal extension (CTE) (reviewed in Ref. 60). The first zinc finger contains the P-box, which is the recognition helix that binds the DNA major groove (Fig. 3Go). By virtue of perfect homology in this P-box, AR, GR, progesterone receptor, and mineralocorticoid receptor are defined as class I nuclear receptors. The second zinc finger contains the D-box, which is the AR dimerization interface. Importantly, a peptide fragment containing only the AR DBD and CTE can perfectly recapitulate the DNA binding site selectivity and specificity as well as dimerization of full-length receptor.


Figure 3
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  		Fig. 3. Structure of the AR DBD Engaged with an Idealized ARE

This figure was generated from coordinates deposited in the Protein Data Bank (1R4I.pdb) and the MBT Protein Workshop application available from the Research Collaboratory for Structural Bioinformatics (85 ). C, C terminus; N, N terminus.

 
Due to the high degree of homology between class I nuclear receptors, an important issue has been how the various nuclear receptors can discriminate between different recognition sequences. An idealized ARE, AGAACAnnnAGAACA, consists of two hexameric direct repeats separated by a three-nucleotide spacer, with the half-site repeated on the same strand. The recent crystal structure of the AR DBD complexed with this prototype ARE revealed that AR unexpectedly binds in a head-to-head conformation (61) (Fig. 3Go). This is in contrast to other nuclear receptor DBDs, which adopt the orientation of the DNA target. The AR head-to-head binding orientation on a direct repeat ARE demonstrates that the strength of the AR dimer interface plays a major role in AR DNA binding site specificity. This also indicates that the principles obtained from study of the AR DBD engaged with a prototype ARE likely extend to the binding of AR to other direct-repeat, and inverted-repeat, palindromes. This has particular importance for PCa, because the best-characterized androgen-regulated genes are not regulated by perfect AREs. For example, the PSA gene is regulated by two AREs in its proximal promoter and a cluster of four AREs in an enhancer region approximately 4 kb upstream of the transcription start site, all of which display different degrees of affinity for the AR DBD (62). In addition, the androgen-regulated TMPRSS2 gene has received great interest recently, as recurrent fusion between TMPRSS2 and members of the Ets family of transcription factors has been identified as an early, and perhaps causative, genomic aberration in PCa (63, 64). Mechanistically, this rearrangement appears to bring expression of the Ets transcription factors ERG, ETV1, or ETV4 under the control of the ARE-regulated TMPRSS2 promoter (65), thus causing aberrant overexpression of these proteins.

The sequence RKcyeagmtlgaRKLKK, which overlaps the DBD D-box, the CTE, and the hinge region, encodes the bipartite AR nuclear localization signal (66). The basic motifs at either end of this sequence have been shown to be critical for AR nuclear import, with the intervening sequence being of little importance. It has been postulated that ligand binding induces a conformational change that makes this nuclear localization signal accessible, thus allowing AR nuclear import. In light of these observations, it is also noteworthy that the lysine residues within the KLKK motif are direct acetylation targets of the p300 and Tip60 acetyltransferases (67, 68).


   STRUCTURE AND FUNCTION OF THE AR NH2-TERMINAL DOMAIN
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The AR NTD is highly flexible and displays intrinsic disorder in solution, which has hampered elucidation of its three-dimensional structure (31, 69, 70, 71). Biophysical study of the NTD has revealed that it exists in a molten globule conformation (70). Thus, the AR NTD could be envisioned as regions of rigid secondary structure, or sticky patches that are either buried or exposed in response to cell type, androgen level, posttranslational modification, expression/activity of binding partners, or chromatin environment. Understanding the dynamic nature of the AR NTD under these various conditions is critically important. For example, the AR NTD accounts for more than 60% of the AR protein and functions as a potent transcriptional activator independent of the CTD. This NTD activity, generally referred to as AR AF-1, contrasts with AF-2, which is a relatively weak transcriptional activation domain in isolation (49, 51, 53). A decline in AF-2 activity relative to AF-1 has been observed for AR and other nuclear receptors during evolution, which may result from an expansion in NTD length (35). Therefore, AR AF-1 is thought to be the major domain responsible for mediating AR transcriptional activity. Indeed, members of the p160 family have been shown to directly bind and activate the AR AF-1 domain (50, 51, 53). In this case of SRC-1, binding is LxxLL independent and requires a glutamine-rich region within the SRC-1 C terminus (51).

Several studies have made progress toward identifying functional regions within the AR NTD and have provided glimpses into the overall mechanisms of AR regulation in PCa and other cell types. The strong transcriptional activity of AF-1 in the AR NTD maps to two large domains, termed transactivation unit (TAU)1 and TAU5. TAU1 and TAU5 were identified originally as the primary transactivation units within the AR NTD after functional deletion analysis of wild-type and CTD-deleted AR in COS-1 and HeLa cells (52). Further deletion studies with rat AR demonstrated that TAU1 could be divided into two discrete transcriptional activation domains, termed AF-1a and AF-1b (72). Transcriptional activity of the AR AF-1a domain has been observed for both rat and human AR in cell lines of various origin (55, 72, 73). Subsequent studies defined the core sequence 178LKDIL (182), resident within a putative NTD helix, as a key motif that can autonomously mediate AR TAU1 transcriptional activity (55, 72). AR AF-1b resembles an acidic activation domain, and deletion of this region from the rat or human AR impairs transcriptional activity in CV-1 and LNCaP cells (72, 73). However, there is no effect of deleting this fragment on AR transcriptional activity in COS-7 cells (55, 73), suggesting context-specific roles for this putative transcriptional activation domain. Similar conflicting findings have been reported for TAU5, with deletion of this fragment either impairing (52, 55, 72) or not affecting (54, 74) AR transcriptional activity. Interestingly, TAU5 appears to be a key module through which SRC-1 and the protein kinase C-related kinase 1 can exert their influence as coactivators (55, 74). Overall, these studies highlight the fact that there are several discrete transcriptional activation domains within the AR NTD. The amorphous nature of the NTD is likely to explain the conflicting reports on the relative roles of these transcriptional activation domains in different cell lines and on different promoters.

In addition to mediating an N/C interaction with the AR AF-2 domain, the FxxLF motif in the AR NTD has been shown to bind the X-chromosome-linked melanoma antigen gene product, MAGE-11 (75). MAGE-11 has been defined as an AR coactivator that stabilizes AR protein and enhances its transcriptional activity. Mechanistically, this appears to result from MAGE-11 competition with AF-2 for binding to FxxLF. For example, MAGE-11 binding to FxxLF increases AF-2 accessibility to LxxLL-containing p160 coactivators such as TIF2 (75). This finding serves as an excellent example of how expression levels of specific coregulator molecules can drastically influence the relative architecture of the AR NTD, and thus the relative activities of AR transcriptional activation domains.

Overlapping the AF-1a LKDIL motif is an LSEASTMQLL (LX7LL) motif, which is evolutionarily conserved among sex steroid receptors. LX7LL serves as a binding site for TAB2 as a component of an NCoR corepressor complex (39). When AR is bound to antiandrogens such as bicalutamide, the TAB2-NCoR corepressor complex binds AR LX7LL, resulting in histone deacetylase-dependent transcriptional repression of AR-regulated promoters such as PSA. However, inflammatory signals initiated by IL-1β stimulate recruitment of MEKK1 kinase to the PSA promoter, which causes the TAB2-NCoR corepressor complex to dissociate from bicalutamide-bound AR (39). As a result of these events, AR derepression occurs, allowing aberrant recruitment of coactivators and subsequent transcriptional activation in the presence of bicalutamide (76). These findings suggest a mechanism by which infiltration of inflammatory cells ultimately influences how the AR NTD modulates the PCa cell response to agonists or antagonists.

Similar to NCoR, SMRT (silencing mediator of retinoid and thyroid receptors) has also been shown to be an important AR corepressor. The AR domain responsible for interaction with SMRT has been mapped to amino acids 171–328 (77). Interestingly, the AR contains two discrete lysine residues, which are situated within two domains conserved among other steroid receptors (385IKLE388 and 519VKSE522) (78). Both K386 and K520 are directly SUMOylated by the E2-conjugating enzyme, Ubc9 (79). Importantly, these modifications inhibit AR activity through a mechanism that may involve SMRT interaction with the AR NTD (77, 78, 79). This provides additional evidence that the AR NTD plays a multifunctional and dynamic role in regulating AR activity.


   STRUCTURE/FUNCTION-BASED RATIONAL STRATEGIES FOR AR INHIBITION IN PCa
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One of the ultimate goals of studying AR structure and function is to design new strategies for inhibiting AR activity. Selective AR modulators, which are AR inhibitors that are more selective for AR expressed in PCa tissue, as opposed to bone, muscle, or other cell types, could serve as a systemic PCa therapy with fewer side effects (reviewed in Ref. 80). However, like antagonists, selective AR modulators would rely on targeting the AR CTD module. Many lines of evidence point to the lack of overall long-term effectiveness of CTD-directed therapies for PCa. More potent and alternative means of AR inhibition would be desirable for PCa treatment because they could, in theory, prevent or delay the emergence of ADI PCa. For example, a recent study demonstrated the effectiveness of short hairpin (sh)RNA-mediated AR ablation for blocking the growth and progression of PCa in vivo. As expected, knockdown of AR expression inhibited LNCaP cell growth in vitro. Furthermore, in established LNCaP xenografts, inducible expression of AR-targeted shRNA was able to elicit a long-term reduction in PSA expression and tumor growth (81). In these experiments, LNCaP tumors developed an ADI phenotype 26 d after castration. However, expression of AR-targeted shRNA prevented the emergence of an ADI phenotype over the entirety of the 55-d experiment (81). Therefore, strategies to eliminate AR protein, either systemically or in a targeted fashion, may serve as an effective long-term treatment for PCa. Alternatively, for disease that has progressed to an ADI phenotype, novel means of AR inhibition could be based on knowledge surrounding mechanisms of AR activation at this stage of the disease. For example, several studies have implicated the AR NTD as a key mediator of ligand-independent AR activity in PCa cells (73, 82, 83, 84). Importantly, a decoy molecule representing the AR NTD inhibited tumor incidence, growth, and hormonal progression in an LNCaP xenograft model of PCa (84). Moreover, intratumor injection of lentivirus expressing the AR NTD decoy fragment inhibited the growth of established LNCaP xenografts. Although these experimental strategies are well suited for therapy of PCa in preclinical model systems and yield important information on the biology of androgen-dependent and ADI PCa, they are not yet at a stage where they would be useful in the clinic. Future improvements will rely on more precise modes of inhibition, e.g. targeting specific NTD transcriptional activation domains with combinations of smaller peptide decoys or drug-like small molecules. These types of approaches would be greatly facilitated by structural knowledge of the entire AR protein.


   SUMMARY
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 SUMMARY
REFERENCES
 
The AR serves as a critical hub for mediating androgen action in normal and cancerous prostate tissue. The organization of the AR is similar to that of other nuclear receptors, as is the overall sequence and three-dimensional structure of the DBD and CTD modules. The NTDs of steroid receptors are highly divergent in sequence, which is likely the basis for differential roles and modes of regulation for these transcription factors. In the case of the AR, the NTD represents approximately 60% of the entire AR protein. Because no structural information is available for this domain, significant details on the mechanisms of AR regulation remain unknown. Overcoming the amorphous nature of the NTD remains a daunting challenge to a complete structural understanding of the AR. Nevertheless, discrete functional motifs within the NTD have been identified and characterized, thus providing important foundations for this pursuit. Future goals should be to 1) identify and characterize the coregulatory protein complexes that communicate with the AR through these motifs; 2) elucidate the role of AR posttranslational modifications in the regulation and activity of functional AR domains; and 3) investigate the modes of communication between functional AR domains. These avenues of investigation should be pursued for all of the physiological stimuli and conditions that have been shown to influence AR activity. These studies could lead to new modes of AR inhibition that would be very different from current systemic PCa therapy, which relies on disrupting the function of the CTD LBD and AF-2 motifs of the AR. Indeed, discrete NTD AF-1 modules could serve as attractive targets for developing novel therapeutics for this disease.


   ACKNOWLEDGMENTS
 
We thank Lucy Schmidt for critical evaluation of this manuscript. Due to space constraints, we were unable to discuss every important contribution to this field.


   FOOTNOTES
 
This work was supported by National Institutes of Health Grants CA121277, DK065236, and CA91956 (to D.J.T.) and the TJ Martell Foundation (to D.J.T.). S.M.D. is a research fellow of the Terry Fox Foundation through a grant from the National Cancer Institute of Canada.

Disclosure Statement: S.M.D. has nothing to declare. D.J.T. consults for GlaxoSmithKline, Inc., and received lecture fees from GTx, Inc., and Takeda Pharmaceutical Co., Ltd.

First Published Online July 17, 2007

Abbreviations: ADI, Androgen depletion-independent; AF, activation function; AR, androgen receptor; ARE, androgen response element; CTD, COOH-terminal domain; DBD, DNA-binding domain; DHT, dihydrotestosterone; LBD, ligand-binding domain; NCoR, nuclear receptor corepressor; NTD, N-terminal domain; PSA, prostate-specific antigen; shRNA, short hairpin RNA; SMRT, silencing mediator of retinoid and thyroid receptor; SRC, steroid receptor coactivator; TAU, transactivation unit; TIF, transcriptional intermediary factor.

Received for publication April 30, 2007. Accepted for publication July 12, 2007.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 AR AND PROSTATE CANCER
 AR STRUCTURAL AND FUNCTIONAL...
 STRUCTURE AND FUNCTION OF...
 STRUCTURE AND FUNCTION OF...
 STRUCTURE AND FUNCTION OF...
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 REFERENCES
 

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NURSA Molecule Pages Link:

Nuclear Receptors:   GR  |  AR
Coregulators:   UBC9  |  SRC-1  |  GRIP1  |  NCOR  |  SMRT
Ligands:   Dihydrotestosterone  |  Diethylstilbestrol  |  Bicalutamide



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