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| Androgen receptor co-regulation in prostate cancer |
Dhirodatta Senapatia,Sangeeta Kumaria,Hannelore V. Heemersa,b,c,*( )
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a Department of Cancer Biology, Cleveland Clinic, Cleveland, OH, USA
b Department of Urology, Cleveland Clinic, Cleveland, OH, USA
c Department of Hematology/Medical Oncology, Cleveland Clinic, Cleveland, OH, USA |
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Abstract Prostate cancer (PCa) progression relies on androgen receptor (AR) action. Preventing AR's ligand-activation is the frontline treatment for metastatic PCa. Androgen deprivation therapy (ADT) that inhibits AR ligand-binding initially induces remission but eventually fails, mainly because of adaptive PCa responses that restore AR action. The vast majority of castration-resistant PCa (CRPC) continues to rely on AR activity. Novel therapeutic strategies are being explored that involve targeting other critical AR domains such as those that mediate its constitutively active transactivation function, its DNA binding ability, or its interaction with co-operating transcriptional regulators. Considerable molecular and clinical variability has been found in AR's interaction with its ligands, DNA binding motifs, and its associated coregulators and transcription factors. Here, we review evidence that each of these levels of AR regulation can individually and differentially impact transcription by AR. In addition, we examine emerging insights suggesting that each can also impact the other, and that all three may collaborate to induce gene-specific AR target gene expression, likely via AR allosteric effects. For the purpose of this review, we refer to the modulating influence of these differential and/or interdependent contributions of ligands, cognate DNA-binding motifs and critical regulatory protein interactions on AR's transcriptional output, which may influence the efficiency of the novel PCa therapeutic approaches under consideration, as co-regulation of AR activity.
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Received: 19 April 2019
Available online: 20 July 2020
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Corresponding Authors:
Hannelore V. Heemers
E-mail: heemerh@ccf.org
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Key determinants of AR transcriptional activity. AR transcriptional output requires ligand activation, binding to cognate DNA binding motifs known as AREs, and interaction with coregulators and secondary transcription factors (interactome). Interactions between these three determinants may fine-tune AR transcription factor function at target genes. AR, androgen receptor; AREs, androgen response elements.
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| Genes | COSMIC | cBIO | | # | ADT-naïve
n=1 976
% | Barbieri
# | ADT-naïve
n=112
% | Fraser
# | ADT-naïve
n=477
% | TCGA
# | ADT-naïve
n=333
% | ADT-naïve
Armenia
# | + CRPC
n=1 013
% | Abida
# | CRPC
n=444
% | Beltran
# | CRPC
n=114
% | ADT-naïve
n=922
average% | CRPC
n=558
average% | | ABCG5 | 9 | 0.46 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 5 | 0.49 | 6 | 1.35 | 1 | 0.88 | 0.00 | 1.11 | | ABCG8 | 5 | 0.25 | 0 | 0.00 | 0 | 0.00 | 1 | 0.30 | 5 | 0.49 | 4 | 0.90 | 0 | 0.00 | 0.10 | 0.45 | | AKR1C1 | 5 | 0.25 | 0 | 0.00 | 0 | 0.00 | 1 | 0.30 | 3 | 0.30 | 1 | 0.23 | 0 | 0.00 | 0.10 | 0.11 | | AKR1C2 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 1 | 0.10 | 2 | 0.45 | 0 | 0.00 | 0.00 | 0.23 | | AKR1C3 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 3 | 0.30 | 1 | 0.23 | 1 | 0.88 | 0.00 | 0.55 | | AKR1C4 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 3 | 0.30 | 2 | 0.45 | 1 | 0.88 | 0.00 | 0.66 | | CYP11A1 | 8 | 0.40 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 2 | 0.20 | 1 | 0.23 | 0 | 0.00 | 0.00 | 0.11 | | CYP11B1 | 8 | 0.40 | 1 | 0.89 | 0 | 0.00 | 0 | 0.00 | 10 | 0.99 | 8 | 1.80 | 2 | 1.75 | 0.30 | 1.78 | | CYP11B2 | 7 | 0.35 | 0 | 0.00 | 0 | 0.00 | 1 | 0.30 | 8 | 0.79 | 6 | 1.35 | 0 | 0.00 | 0.10 | 0.68 | | CYP17A1 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 2 | 0.20 | 1 | 0.23 | 0 | 0.00 | 0.00 | 0.11 | | CYP19A1 | 7 | 0.35 | 0 | 0.00 | 2 | 0.42 | 1 | 0.30 | 3 | 0.30 | 1 | 0.23 | 0 | 0.00 | 0.24 | 0.11 | | CYP1A1 | 5 | 0.25 | 1 | 0.89 | 0 | 0.00 | 1 | 0.30 | 5 | 0.49 | 2 | 0.45 | 1 | 0.88 | 0.40 | 0.66 | | CYP1B1 | 4 | 0.20 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 3 | 0.30 | 4 | 0.90 | 0 | 0.00 | 0.00 | 0.45 | | CYP21A2 | 8 | 0.40 | 0 | 0.00 | 0 | 0.00 | 1 | 0.30 | 3 | 0.30 | 2 | 0.45 | 0 | 0.00 | 0.10 | 0.23 | | CYP3A4 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 3 | 0.30 | 1 | 0.23 | 0 | 0.00 | 0.00 | 0.11 | | CYP3A43 | 2 | 0.10 | 0 | 0.00 | 0 | 0.00 | 2 | 0.60 | 3 | 0.30 | 2 | 0.45 | 0 | 0.00 | 0.20 | 0.23 | | CYP3A5 | 2 | 0.10 | 1 | 0.89 | 1 | 0.21 | 0 | 0.00 | 4 | 0.39 | 1 | 0.23 | 1 | 0.88 | 0.37 | 0.55 | | CYP3A7 | 3 | 0.15 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 2 | 0.20 | 1 | 0.23 | 0 | 0.00 | 0.00 | 0.11 | | HSD17B1 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 1 | 0.10 | 0 | 0.00 | 1 | 0.88 | 0.00 | 0.44 | | HSD17B10 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0.00 | 0.00 | | HSD17B11 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 2 | 0.60 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0.20 | 0.00 | | HSD17B12 | 2 | 0.10 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0.00 | 0.00 | | HSD17B13 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0.00 | 0.00 | | HSD17B14 | 2 | 0.10 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 2 | 0.20 | 2 | 0.45 | 1 | 0.88 | 0.00 | 0.66 | | HSD17B2 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 3 | 0.30 | 3 | 0.68 | 0 | 0.00 | 0.00 | 0.34 | | HSD17B3 | 14 | 0.71 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 4 | 0.39 | 2 | 0.45 | 0 | 0.00 | 0.00 | 0.23 | | HSD17B4 | 4 | 0.20 | 0 | 0.00 | 0 | 0.00 | 1 | 0.30 | 5 | 0.49 | 3 | 0.68 | 0 | 0.00 | 0.10 | 0.34 | | HSD17B6 | 2 | 0.10 | 0 | 0.00 | 1 | 0.21 | 0 | 0.00 | 2 | 0.20 | 1 | 0.23 | 1 | 0.88 | 0.07 | 0.55 | | HSD17B7 | 2 | 0.10 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 1 | 0.23 | 0 | 0.00 | 0.00 | 0.11 | | HSD17B8 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 1 | 0.10 | 0 | 0.00 | 0 | 0.00 | 0.00 | 0.00 | | HSD3B1 | 5 | 0.25 | 0 | 0.00 | 0 | 0.00 | 1 | 0.30 | 2 | 0.20 | 0 | 0.00 | 0 | 0.00 | 0.10 | 0.00 | | HSD3B2 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 1 | 0.30 | 3 | 0.30 | 1 | 0.23 | 0 | 0.00 | 0.10 | 0.11 | | HSD3B7 | 6 | 0.30 | 1 | 0.89 | 0 | 0.00 | 0 | 0.00 | 4 | 0.39 | 2 | 0.45 | 0 | 0.00 | 0.30 | 0.23 | | RDH15 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 1 | 0.10 | 1 | 0.23 | 0 | 0.00 | 0.00 | 0.11 | | RDH16 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 3 | 0.30 | 2 | 0.45 | 0 | 0.00 | 0.00 | 0.23 | | RDH5 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0.00 | 0.00 | | SHBG | 2 | 0.10 | 0 | 0.00 | 0 | 0.00 | 1 | 0.30 | 1 | 0.10 | 1 | 0.23 | 0 | 0.00 | 0.10 | 0.11 | | SLCO1A2 | 5 | 0.25 | 0 | 0.00 | 1 | 0.21 | 0 | 0.00 | 6 | 0.59 | 2 | 0.45 | 0 | 0.00 | 0.07 | 0.23 | | SLCO1B1 | 6 | 0.30 | 0 | 0.00 | 1 | 0.21 | 1 | 0.30 | 4 | 0.39 | 0 | 0.00 | 0 | 0.00 | 0.17 | 0.00 | | SLCO1B3 | 5 | 0.25 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 2 | 0.20 | 1 | 0.23 | 0 | 0.00 | 0.00 | 0.11 | | SLCO1C1 | 5 | 0.25 | 0 | 0.00 | 0 | 0.00 | 1 | 0.30 | 4 | 0.39 | 1 | 0.23 | 0 | 0.00 | 0.10 | 0.11 | | SLCO2A1 | 5 | 0.25 | 1 | 0.89 | 0 | 0.00 | 1 | 0.30 | 4 | 0.39 | 5 | 1.13 | 0 | 0.00 | 0.40 | 0.56 | | SLCO2B1 | 7 | 0.35 | 0 | 0.00 | 0 | 0.00 | 1 | 0.30 | 8 | 0.79 | 3 | 0.68 | 6 | 5.26 | 0.10 | 2.97 | | SLCO3A1 | 18 | 0.91 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 9 | 0.89 | 3 | 0.68 | 1 | 0.88 | 0.00 | 0.78 | | SLCO4A1 | 9 | 0.46 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 5 | 0.49 | 3 | 0.68 | 2 | 1.75 | 0.00 | 1.22 | | SLCO4C1 | 8 | 0.40 | 4 | 3.57 | 1 | 0.21 | 0 | 0.00 | 12 | 1.18 | 5 | 1.13 | 0 | 0.00 | 1.26 | 0.56 | | SLCO5A1 | 11 | 0.56 | 0 | 0.00 | 0 | 0.00 | 1 | 0.30 | 5 | 0.49 | 5 | 1.13 | 0 | 0.00 | 0.10 | 0.56 | | SLCO6A1 | 12 | 0.61 | 1 | 0.89 | 0 | 0.00 | 1 | 0.30 | 14 | 1.38 | 9 | 2.03 | 0 | 0.00 | 0.40 | 1.01 | | SRD5A1 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0.00 | 0.00 | | SRD5A2 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0.00 | 0.00 | | SRD5A3 | 3 | 0.15 | 0 | 0.00 | 1 | 0.21 | 0 | 0.00 | 3 | 0.30 | 3 | 0.68 | 0 | 0.00 | 0.07 | 0.34 | | STAR | 3 | 0.15 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 2 | 0.20 | 2 | 0.45 | 1 | 0.88 | 0.00 | 0.66 | | UGT2B15 | 2 | 0.10 | 0 | 0.00 | 0 | 0.00 | 3 | 0.90 | 3 | 0.30 | 0 | 0.00 | 0 | 0.00 | 0.30 | 0.00 | | UGT2B17 | 3 | 0.15 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 4 | 0.39 | 0 | 0.00 | 0 | 0.00 | 0.00 | 0.00 | | UGT2B7 | 2 | 0.10 | 0 | 0.00 | 2 | 0.42 | 1 | 0.30 | 7 | 0.69 | 1 | 0.23 | 1 | 0.88 | 0.24 | 0.55 |
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Somatic mutations in steroidogenic genes in clinical PCa tissues. COSMIC and cBIO databases were queried for somatic mutations in genes that encode protein involved in the synthesis, metabolism, and transport of androgens [28]. The COSMIC database was queried via the Cancer browser, selecting for “prostate cancer” and “carcinoma” histology, and retrieving only data from genome-wide sequencing efforts. For cBIO analysis, datasets analyses are marked by first author of study that was examined.
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| Genes | COSMIC | cBIO | | # | ADT-naïve
n=1 976
% | Barbieri
# | ADT-naïve
n=112
% | Fraser
# | ADT-naïve
n=477
% | TCGA
# | ADT-naïve
n=333
% | ADT-naïve
Armenia
# | + CRPC
n=1 013
% | Abida
# | CRPC
n=444
% | Beltran
# | CRPC
n=114
% | ADT-naïve
n=922
average% | CRPC
n=558
average% | | NCOA1 | 10 | 0.51 | 0 | 0.00 | 0 | 0.00 | 2 | 0.60 | 6 | 0.59 | 2 | 0.45 | 0 | 0.00 | 0.20 | 0.23 | | NCOA2 | 9 | 0.46 | 2 | 1.79 | 1 | 0.21 | 1 | 0.30 | 8 | 0.79 | 4 | 0.90 | 0 | 0.00 | 0.77 | 0.45 | | NCOA3 | 11 | 0.56 | 1 | 0.89 | 3 | 0.63 | 2 | 0.60 | 6 | 0.59 | 2 | 0.45 | 1 | 0.88 | 0.71 | 0.66 | | NCOA4 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 2 | 0.60 | 3 | 0.30 | 1 | 0.23 | 0 | 0.00 | 0.20 | 0.11 | | NCOA6 | 17 | 0.86 | 1 | 0.89 | 1 | 0.21 | 2 | 0.60 | 10 | 0.99 | 4 | 0.90 | 0 | 0.00 | 0.57 | 0.45 | | NCOR1 | 19 | 0.96 | 2 | 1.79 | 4 | 0.84 | 6 | 1.80 | 26 | 2.57 | 13 | 2.93 | 2 | 1.75 | 1.48 | 2.34 | | NCOR2 | 28 | 1.42 | 1 | 0.89 | 1 | 0.21 | 0 | 0.00 | 23 | 2.27 | 14 | 3.15 | 1 | 0.88 | 0.37 | 2.02 |
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Somatic mutations in AR-associated NCoA and NCoR coregulators in clinical PCa. COSMIC and cBio databases were queried for somatic mutations in genes that encode AR-associated NCoAs and NCoRs (28). The COSMIC database was queried via the Cancer browser, selecting for “prostate cancer” and “carcinoma” histology, and retrieving only data from genome-wide sequencing efforts. For cBIO analysis, datasets analyses are marked by first author of study that was examined.
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Cooperativity and interdependence between key determinants of AR transcriptional activity are consistent with allosteric regulation of AR action. Schematic representation of variability in AR ligands, AR interactome, and ARE(s) and their influence on one another (outer circle) and their convergence on allosteric regulation of AR, which may exist as different forms (inner circle). ADT, androgen deprivation therapy; AR, androgen receptor; ARE, androgen response element; SARM, selective androgen receptor modulators.
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