{"gene":"AR","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2002,"finding":"AR functions as a ligand-activated transcription factor; coregulators influence AR ligand selectivity, DNA binding capacity, histone modification, and recruitment of basal transcriptional machinery. The AR N-terminal domain recruits coactivators via mechanisms distinct from other steroid receptors, correlating with the low affinity of the ligand-binding domain for canonical LxxLL-bearing coactivators.","method":"Review of functional studies including domain mutagenesis, transactivation assays, coregulator interaction studies","journal":"Endocrine reviews","confidence":"High","confidence_rationale":"Tier 2 / Strong — synthesis of multiple independent labs' biochemical and functional studies establishing core AR transcriptional mechanism","pmids":["11943742","17940184","12612376"],"is_preprint":false},{"year":2002,"finding":"PAK6 (p21-activated kinase 6) was cloned as an AR-interacting protein; it binds in vitro to the hinge region between the AR DNA- and ligand-binding domains without requiring ligand. PAK6 kinase activity is stimulated by AR binding. PAK6 inhibits AR transcriptional activity in transient transfection assays with episomal and integrated reporters, and is primarily cytoplasmic.","method":"Yeast two-hybrid/mammalian one-hybrid, in vitro binding assay, transient transfection reporter assay, in vitro kinase assay, subcellular localization by epitope tagging","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays plus functional kinase and transcription assays in single lab","pmids":["11773441"],"is_preprint":false},{"year":2002,"finding":"DAX-1 (NROB1) directly interacts with AR and potently inhibits ligand-dependent AR transcriptional activation as well as the AR N-terminal/C-terminal (N/C) domain interaction. The interaction involves the N-terminal repeat domain of DAX-1 and the C-terminal ligand-binding/activation domain of AR. DAX-1 can relocalize AR in both cytoplasm and nucleus, suggesting intracellular tethering contributes to inhibition.","method":"Co-immunoprecipitation, GST pull-down, transactivation reporter assay, subcellular localization imaging","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated with pull-down and Co-IP, functional inhibition confirmed in transcription assays, single lab","pmids":["11875111"],"is_preprint":false},{"year":2008,"finding":"AR acts as a master regulator of G1-S phase progression in prostate cancer cells, inducing signals that promote G1 cyclin-dependent kinase (CDK) activity, leading to phosphorylation and inactivation of the retinoblastoma tumor suppressor (RB), thereby governing androgen-dependent proliferation.","method":"Cell cycle analysis, loss-of-function experiments, phosphorylation assays for RB in prostate cancer cell lines","journal":"Nuclear receptor signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection in cell lines by multiple groups, RB phosphorylation as defined readout","pmids":["18301781"],"is_preprint":false},{"year":2008,"finding":"The AR ligand-binding domain has low intrinsic transactivation properties correlating with low affinity for canonical LxxLL-bearing coactivators; instead, AR transcriptional activation involves alternative recruitment of coactivators to the N-terminal domain and hinge region. A strong ligand-induced N-terminal/C-terminal (N/C) intramolecular interaction is involved in many aspects of AR function as a transcription factor.","method":"Domain mutagenesis, transactivation reporter assays, interaction studies with LxxLL coactivators","journal":"Nuclear receptor signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structure-function analysis with mutagenesis replicated across multiple labs","pmids":["18612376"],"is_preprint":false},{"year":2008,"finding":"Protein kinase D1 (PKD1) forms a protein complex with AR in prostate cancer cells and is associated with the AR transcriptional complex at the PSA gene promoter. Both wild-type and kinase-dead PKD1 attenuate ligand-dependent AR transcriptional activation, while PKD1 knockdown enhances it.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP) at PSA promoter, transactivation reporter assay, siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus functional reporter assay, single lab","pmids":["18602367"],"is_preprint":false},{"year":2010,"finding":"CDK9 phosphorylates AR at serine 81 (S81) in vitro and in cells; this is the highest stoichiometric phosphorylation on AR in response to hormone. CDK9 knockdown or pharmacological inhibition reduces S81 phosphorylation and AR transcriptional activity. Loss of S81 phosphorylation (S81A mutant) limits prostate cancer cell growth and alters AR promoter selectivity for endogenous target genes.","method":"In vitro kinase assay with mass spectrometry, siRNA knockdown, pharmacological inhibition (DRB, Flavopiridol), stable cell lines with wild-type vs. S81A mutant AR, endogenous target gene expression analysis","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus mutagenesis plus cellular validation with multiple inhibitor approaches in single rigorous study","pmids":["20980437"],"is_preprint":false},{"year":2006,"finding":"Hic-5/ARA55 functions as a prostate stroma-specific AR coactivator; its expression influences androgen-induced keratinocyte growth factor (KGF) expression in WPMY-1 prostate stromal cells.","method":"Expression analysis in stromal vs. epithelial cells, functional transcription assay for KGF induction","journal":"Steroids","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic follow-up reported in abstract","pmids":["17166536"],"is_preprint":false},{"year":2016,"finding":"AR is required for maximum ER genomic binding in ER+/AR+ breast cancer cells; estradiol induces AR chromatin binding at sites enriched for estrogen response elements that overlap with ER-binding sites. AR inhibition (enzalutamide, MJC13) reduces baseline and estradiol-mediated proliferation and synergizes with tamoxifen and fulvestrant.","method":"ChIP-seq for AR chromatin binding, anti-androgen inhibition (enzalutamide/MJC13), cell proliferation assays, in vivo xenograft models","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus functional cell and in vivo studies in single lab with multiple orthogonal approaches","pmids":["27565181"],"is_preprint":false},{"year":2018,"finding":"AR membrane transport to the plasma membrane is microtubule-dependent and mediated by the motor protein KIF5B; disruption of KIF5B function interferes with AR membrane association. AR physically interacts with KIF5B, and androgen enhances this interaction. Membrane-associated AR activates HSP27, which mediates membrane-to-nuclear signal transduction to potentiate nuclear AR transcriptional activity.","method":"Co-immunoprecipitation, GST pull-down, microtubule disruption assays, KIF5B knockdown, subcellular fractionation, HSP27 functional assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and pull-down plus functional KIF5B knockdown and HSP27 pathway analysis, single lab","pmids":["29934310"],"is_preprint":false},{"year":2019,"finding":"AKR1C3 increases AR-V7 protein stability in enzalutamide-resistant prostate cancer cells through activation of the ubiquitin-mediated proteasome pathway; indomethacin (AKR1C3 inhibitor) decreases AR/AR-V7 protein expression in vitro and in vivo via ubiquitin-proteasome pathway activation.","method":"Western blot protein stability assay, ubiquitin assay, pharmacological inhibition with indomethacin, in vivo xenograft model","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic ubiquitination assays plus in vitro and in vivo validation, single lab","pmids":["31308078"],"is_preprint":false},{"year":2017,"finding":"Aurora kinase A (AURKA) phosphorylates the E3 ligase CHIP at S273, activating its E3 ligase activity toward AR. The 2-methoxyestradiol→Aurora A→CHIP→AR pathway promotes proteasomal degradation of AR; cells expressing CHIP S273A mutant show attenuated AR degradation, confirming this phosphorylation is required.","method":"In vitro kinase assay, site-directed mutagenesis (CHIP S273A), AURKA inhibitors and RNAi knockdown, AR ubiquitination and degradation assays","journal":"Molecular cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis validation plus RNAi and pharmacological confirmation, single rigorous study","pmids":["28536143"],"is_preprint":false},{"year":2020,"finding":"KIF15 directly binds the N-terminus of AR/AR-V7 and prevents AR/AR-V7 protein degradation by increasing the association of deubiquitinase USP14 with AR/AR-V7; in turn, transcriptionally active AR stimulates KIF15 expression, forming a reciprocal activation loop.","method":"Co-immunoprecipitation, direct binding assay, protein stability assay, ubiquitination assay, ChIP for AR at KIF15 locus","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for binding, functional ubiquitination assay, reciprocal transcriptional regulation confirmed, single lab","pmids":["33277366"],"is_preprint":false},{"year":2020,"finding":"DOT1L histone methyltransferase marks a distal enhancer in the MYC gene with H3K79 methylation; this enhancer is bound by AR and DOT1L specifically in AR-positive prostate cancer cells. DOT1L inhibition reduces MYC expression, upregulates E3 ubiquitin ligases HECTD4 and MYCBP2, and promotes AR and MYC degradation in a negative feedforward loop.","method":"ChIP-seq, genetic and chemical inhibition of DOT1L, AR-positive vs. AR-negative cell comparison, ubiquitin ligase expression analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus genetic/chemical inhibition with mechanistic downstream pathway analysis, single lab","pmids":["32814769"],"is_preprint":false},{"year":2021,"finding":"A cryptic transactivation domain of EZH2 (EZH2TAD) directly binds both AR and constitutively active AR splice variant AR-V7, mediating assembly and recruitment of transactivation-related machineries at genomic sites that lack PRC2 binding (non-canonical EZH2 function). EZH2TAD is required for chromatin recruitment of EZH2 to oncogenes and for EZH2-mediated oncogene activation in prostate cancer.","method":"Co-immunoprecipitation, ChIP-seq, domain mutagenesis, PROTAC depletion (MS177), in vitro and in vivo functional assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain binding characterization with Co-IP/mutagenesis, ChIP-seq, and in vivo validation in single rigorous study","pmids":["36300627"],"is_preprint":false},{"year":2022,"finding":"METTL3 epigenetically represses AR expression in cardiac fibroblasts via m6A modification of AR mRNA in an m6A-YTHDF2-dependent manner; decreased AR expression activates HIF-1α signaling, enhancing glycolysis and cardiac fibroblast proliferation. AR interacts with HIF-1α and its overexpression reduces HIF-1α axis and inhibits glycolysis.","method":"RNA m6A sequencing, METTL3 knockdown/overexpression, Co-IP for AR-HIF-1α interaction, glycolysis assays, in vivo cardiac fibrosis model","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A sequencing plus Co-IP plus gain/loss-of-function, single lab","pmids":["36370857"],"is_preprint":false},{"year":2022,"finding":"NSUN2 posttranscriptionally stabilizes AR mRNA through cluster m5C modification in a m5C-YBX1-dependent manner; NSUN2 depletion decreases AR and AR-V7 expression and activity. AR transcriptionally regulates NSUN2, forming a positive feedback loop. YBX1 binds to AR m5C sites as confirmed by RIP-qPCR and EMSA.","method":"RNA bisulfite sequencing (RNA-BisSeq), in vitro enzyme reaction assay, RIP-qPCR, EMSA, ChIP, luciferase assay for AR binding to NSUN2 promoter","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic modification assay, RNA-BisSeq, and multiple binding assays, single lab","pmids":["36169095"],"is_preprint":false},{"year":2022,"finding":"AR mRNA translation is coordinately regulated by RNA-binding proteins YTHDF3 and G3BP1: m6A-modified AR mRNA is bound by YTHDF3 and translationally stimulated under ambient conditions, while m6A-unmodified AR mRNA is bound by G3BP1 and translationally repressed. Under AR pathway inhibition stress, m6A-modified AR mRNA recruits to stress granules (SGs) where it undergoes liquid-liquid phase separation with YTHDF3, reducing translation.","method":"Polysome profiling, RNA-protein interaction assay, stress granule imaging, m6A sequencing, YTHDF3/G3BP1 silencing","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polysome and SG fractionation plus RNA-protein binding assays and m6A modification analysis, single lab with multiple orthogonal methods","pmids":["34939643"],"is_preprint":false},{"year":2021,"finding":"ENZ-resistant CRPC cells acquire non-canonical AR binding sites (ARBS-gained) lacking canonical androgen response elements (ARE) and FOXA1 motifs, which are enriched with CpG islands and binding sites for CXXC5 and TET2. ARBS-gained loci are enriched with H3K27ac, and ENZ-resistant cells are hypersensitive to BET/CBP-p300 dual inhibition.","method":"Genome-wide ChIP-seq, RNA-seq, patient-derived xenografts, pharmacological inhibition with NEO2734","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and RNA-seq with PDX validation, single lab","pmids":["33750801"],"is_preprint":false},{"year":2022,"finding":"OTUD6A deubiquitinase stabilizes AR by erasing K11-linked polyubiquitination of AR; catalytically inactive OTUD6A mutant fails to stabilize AR. OTUD6A also stabilizes Brg1 (SWI/SNF ATPase subunit) by erasing K27-linked polyubiquitination.","method":"Mass spectrometry substrate identification, Co-immunoprecipitation, ubiquitination assays with linkage-specific analysis, catalytically inactive mutant, in vivo xenograft models","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS-based substrate identification, specific ubiquitin linkage characterization, mutagenesis, and in vivo validation in single rigorous study","pmids":["35233061"],"is_preprint":false},{"year":2018,"finding":"CNPY2 controls AR protein levels by inhibiting MYLIP (an E3 ubiquitin ligase)-mediated AR ubiquitination and proteasomal degradation; CNPY2 decreases MYLIP ubiquitination activity by inhibiting the interaction between MYLIP and E2 ubiquitin ligase UBE2D1.","method":"Ubiquitination assay, Co-immunoprecipitation, CNPY2 knockdown/overexpression, proteasome inhibitor treatment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic ubiquitination pathway dissection with Co-IP and E2/E3 interaction assays, single lab","pmids":["29707137"],"is_preprint":false},{"year":2021,"finding":"AR directly regulates transcription of succinate dehydrogenase catalytic subunit genes (SDHA, SDHB) via androgen response elements (AREs). AR pathway inhibition suppresses SDH activity, causing succinate accumulation; succinate triggers calcium release, which phospho-activates HSP27 via CaMKK2/AMPK/p38 axis, stabilizing and reactivating AR protein.","method":"ChIP for AR at SDHA/SDHB AREs, SDH enzyme activity assay, calcium imaging, pharmacological kinase inhibition, AR protein stability assay, tissue microarray validation","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct ChIP evidence for AR-ARE interaction, biochemical pathway dissection with enzymatic assays and kinase inhibition, tissue validation; multiple orthogonal methods in single study","pmids":["33709547"],"is_preprint":false},{"year":2014,"finding":"MEIS1 homeodomain transcription factor directly interacts with AR (identified by Co-IP and GST pull-down) and inhibits AR transcriptional activity, reduces AR target gene expression, modulates AR cytoplasm/nucleus translocation, and promotes recruitment of corepressors NCoR and SMRT to the AR complex in the presence of androgen.","method":"Co-immunoprecipitation, GST pull-down, transactivation reporter assay, subcellular localization assay, ChIP for AR at PSA promoter","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays plus multiple functional assays including ChIP, single lab","pmids":["25158280"],"is_preprint":false},{"year":2019,"finding":"DUSP22 interacts with AR as a regulatory partner, dephosphorylates AR at Tyr534 to interfere with EGF-induced AR phosphorylation, and suppresses PSA gene expression through phosphatase-dependent pathways. DUSP22 also dephosphorylates EGFR and its downstream ERK1/2 signaling.","method":"Co-immunoprecipitation, phosphorylation assay (Tyr534 AR), DUSP22 overexpression/loss-of-function, PSA reporter assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus site-specific phosphorylation assay plus functional reporter, single lab","pmids":["31693867"],"is_preprint":false},{"year":2016,"finding":"AR has an expanded repertoire of transcriptional targets in actively cycling prostate cancer cells, segregating into cell-cycle-common and phase-restricted AR functions. AR regulates dihydroceramide desaturase 1 specifically in mitotically active cells, promoting pro-metastatic phenotypes.","method":"AR ChIP-seq as a function of cell cycle phase, gene expression profiling, functional assays for pro-metastatic phenotypes","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell cycle-resolved ChIP-seq plus functional validation, single lab","pmids":["27669432"],"is_preprint":false},{"year":2022,"finding":"AR-EZH2 protein interaction is impaired by pre-castration androgen levels but recovered by post-castration androgen levels; AR overexpression alone with low androgen can rapidly redistribute AR chromatin binding and activate a distinct transcription program enriched for DNA damage repair pathways, with EZH2 involvement in this reprogramming.","method":"Co-IP for AR-EZH2 interaction, inducible AR overexpression model, ChIP-seq cistrome analysis, RNA-seq, bioinformatic prediction","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with androgen-level modulation plus ChIP-seq and RNA-seq, single lab","pmids":["36408179"],"is_preprint":false},{"year":2023,"finding":"AR activates YAP translation and induces transcription of the TAZ-encoding gene WWTR1 in prostate cancer, differentially regulating these two Hippo pathway effectors. AR-mediated YAP/TAZ activation is regulated by the RhoA transcriptional mediator SRF. YAP/TAZ are not essential for sustaining AR activity.","method":"Androgen stimulation, AR inhibition, translational reporter assay, transcription assay, SRF manipulation, anchorage-independent growth assays","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — translational vs. transcriptional distinction established experimentally, SRF pathway validated, single lab","pmids":["37385752"],"is_preprint":false},{"year":2017,"finding":"Vav3 DH domain directly interacts with the N-terminal region of AR-V7 (and full-length AR); Vav3 DH domain expression disrupts Vav3-AR-V7 interaction and inhibits Vav3 enhancement of AR-V7 activity, also disrupting AR-V7 interaction with coactivators SRC1 and Vav2. Disruption of AR-V7/coactivator interaction decreases AR-V7 nuclear levels.","method":"Mutational and biochemical domain interaction studies, Co-IP, transcriptional reporter assays, functional cell proliferation and anchorage-independent growth assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis plus biochemical binding plus multiple functional readouts, single lab","pmids":["28811363"],"is_preprint":false},{"year":2020,"finding":"ACK1 (oncogenic tyrosine kinase) phosphorylates histone H4, leading to epigenetic upregulation of AR expression as a mechanism of castration-resistant prostate cancer resistance to anti-androgens.","method":"Kinase assay, chromatin analysis of H4 phosphorylation at AR locus, ACK1-selective inhibitor (R)-9b","journal":"NAR cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic detail available in abstract","pmids":["32885168"],"is_preprint":false},{"year":2022,"finding":"AR-V7 and full-length AR display distinct cistromes with numerous differential chromatin binding sites in prostate cancer cells; AR-V7 preferential binding sites are enriched for a half-ARE de novo motif and are located proximal to transcription start sites, without FOXA1 enrichment, distinguishing them from canonical half-ARE AR-V7 sites.","method":"ChIP-seq for AR and AR-V7 at matched expression levels in LNCaP and VCaP cells, de novo motif analysis, RNA-seq transcriptome comparison","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — controlled ChIP-seq with matched receptor levels plus RNA-seq, single lab","pmids":["35354884"],"is_preprint":false},{"year":2015,"finding":"AR binds to androgen response elements (AREs) in the miR-145 promoter and suppresses p53-induced miR-145 expression; decreased miR-145 leads to upregulation of HIF2α/VEGF/MMP9/CCND1 in renal cell carcinoma, promoting tumor progression independent of VHL status.","method":"ChIP for AR at miR-145 promoter ARE, luciferase reporter assay, AR-shRNA knockdown, miR-145 mimic rescue, orthotopic xenograft mouse model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter plus in vivo rescue experiment, single lab","pmids":["26304926"],"is_preprint":false},{"year":2021,"finding":"AR directly regulates HCC cell migration and invasion via a miR-325/ACP5 signaling axis; AR transcriptionally regulates miR-325, which directly targets the 3'UTR of ACP5 mRNA to suppress its translation and reduce cell migration/invasion.","method":"AR knockdown, miR-325 overexpression, 3'UTR luciferase reporter assay for ACP5, in vivo orthotopic xenograft model","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR reporter validates direct miRNA-target interaction, AR transcriptional regulation plus in vivo validation, single lab","pmids":["33753989"],"is_preprint":false},{"year":2018,"finding":"CpG methylation of the proximal AR promoter inversely correlates with AR mRNA expression; a 158-bp region containing two consecutive CpGs is sufficient to suppress reporter gene expression when methylated. RUNX1 binds this region and ectopic RUNX1 expression inhibits reporter gene expression through this region, identifying it as a regulator of AR transcription.","method":"Bisulfite sequencing of AR promoter, luciferase reporter assay with methylated template, RUNX1 ChIP and ectopic expression in HEK293T cells","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — methylation-reporter mechanistic assay plus RUNX1 binding and functional validation, single lab","pmids":["30124873"],"is_preprint":false},{"year":2020,"finding":"Sex-associated expression analysis in lungs showed that ACE2 and AR expression are sexually dimorphic and higher in males; ACE2 expression is moderately suppressible by enzalutamide (AR antagonist) in male mice. TMPRSS2 expression in lungs was not increased in males vs. females and was not decreased by enzalutamide treatment (negative result for TMPRSS2-AR regulation in lung).","method":"Comparative gene expression in human and mouse lungs, pharmacological AR antagonism with enzalutamide in male mice","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, expression analysis with pharmacological intervention but limited mechanistic mechanistic follow-up","pmids":["33083800"],"is_preprint":true}],"current_model":"AR (androgen receptor, NR3C4) is a ligand-activated nuclear transcription factor that, upon androgen binding, undergoes a conformational change involving a strong N-terminal/C-terminal intramolecular interaction, translocates to the nucleus (via microtubule/KIF5B-dependent membrane-associated intermediate), binds androgen response elements (AREs) or non-canonical chromatin sites, and recruits diverse coactivators (including through its N-terminal domain rather than canonical LxxLL surfaces) and corepressors to regulate target gene transcription; its activity is modulated by phosphorylation (CDK9 at S81, EGFR-induced Tyr534), ubiquitin-mediated proteasomal degradation (via E3 ligases MYLIP, CHIP, and deubiquitinases USP14, USP22, OTUD6A), m6A/m5C mRNA modification (METTL3/YTHDF2 and NSUN2/YBX1), direct binding of coregulators (PAK6, DAX-1, PKD1, MEIS1, Hic-5/ARA55, EZH2TAD, Vav3, DOT1L), and directly drives G1-S cell cycle progression via CDK activation and RB phosphorylation in prostate cancer; AR also directly regulates metabolic gene expression including succinate dehydrogenase subunits, and non-genomically activates HSP27 at the membrane to potentiate nuclear transcriptional activity."},"narrative":{"mechanistic_narrative":"AR (NR3C4) is a ligand-activated nuclear transcription factor that governs androgen-dependent gene expression programs, most prominently driving G1-S cell cycle progression in prostate cancer through induction of G1 cyclin-dependent kinase activity and inactivating phosphorylation of RB [PMID:11943742, PMID:17940184, PMID:12612376, PMID:18301781]. Unlike other steroid receptors, AR's ligand-binding domain has weak intrinsic transactivation and low affinity for canonical LxxLL coactivators; productive transcription instead depends on a strong ligand-induced N-terminal/C-terminal intramolecular interaction and on coactivator recruitment to the N-terminal domain and hinge region [PMID:11943742, PMID:17940184, PMID:12612376, PMID:18612376]. AR binds androgen response elements as well as non-canonical chromatin sites — including ENZ-resistance-associated sites lacking AREs and FOXA1 motifs and distinct AR-V7 cistromes enriched for half-ARE motifs — to direct context-specific transcriptional outputs [PMID:33750801, PMID:35354884]. AR target genes extend to metabolic regulators such as succinate dehydrogenase subunits SDHA/SDHB, whose suppression triggers a succinate/calcium/HSP27 feedback loop that reactivates AR protein [PMID:33709547], and to microRNA-mediated programs (miR-145, miR-325) controlling tumor progression in renal and hepatocellular carcinoma [PMID:26304926, PMID:33753989]. AR activity is shaped by phosphorylation (CDK9 at S81, which sets the highest-stoichiometry hormone-induced phosphorylation and controls promoter selectivity [PMID:20980437]; reversal of EGF-induced Tyr534 phosphorylation by DUSP22 [PMID:31693867]) and by direct coregulator binding, including the kinase PKD1 [PMID:18602367], homeodomain factor MEIS1 which recruits NCoR/SMRT corepressors [PMID:25158280], and a cryptic EZH2 transactivation domain that recruits AR and AR-V7 to oncogenes independent of PRC2 [PMID:36300627]. AR protein abundance is set by a network of E3 ligases and deubiquitinases: CHIP activated by Aurora A phosphorylation and MYLIP (counteracted by CNPY2) drive degradation, while OTUD6A (erasing K11-linked ubiquitin) and USP14 (recruited via KIF15) stabilize AR and AR-V7 [PMID:28536143, PMID:35233061, PMID:29707137, PMID:33277366]. AR also undergoes membrane-associated, microtubule/KIF5B-dependent trafficking that activates HSP27 to potentiate nuclear transcription [PMID:29934310], and its mRNA is post-transcriptionally controlled by m6A (METTL3/YTHDF2, YTHDF3/G3BP1) and m5C (NSUN2/YBX1) modifications [PMID:36370857, PMID:36169095, PMID:34939643].","teleology":[{"year":2002,"claim":"Established that AR is a ligand-activated transcription factor with a non-canonical coactivator-recruitment mechanism, explaining why its weak ligand-binding domain depends on the N-terminal domain for transactivation.","evidence":"Synthesis of domain mutagenesis, transactivation, and coregulator interaction studies","pmids":["11943742","17940184","12612376"],"confidence":"High","gaps":["Does not resolve which coactivator surfaces engage the N-terminal domain","Mechanism of ligand selectivity by coregulators not defined"]},{"year":2002,"claim":"Identified PAK6 and DAX-1 as direct AR-interacting inhibitors, showing AR transcriptional output is restrained by partners acting through the hinge and the N/C interaction respectively.","evidence":"Yeast/mammalian two-hybrid, GST pull-down, Co-IP, kinase and reporter assays","pmids":["11773441","11875111"],"confidence":"Medium","gaps":["PAK6 kinase substrate on AR not identified","Physiological significance of DAX-1 tethering in vivo unestablished"]},{"year":2008,"claim":"Defined AR as a master regulator of G1-S progression, linking androgen signaling to CDK-mediated RB inactivation and androgen-dependent proliferation.","evidence":"Cell cycle analysis, loss-of-function, RB phosphorylation assays in prostate cancer lines","pmids":["18301781"],"confidence":"Medium","gaps":["Direct AR target genes mediating CDK activation not fully enumerated","Connection to specific cyclins unresolved"]},{"year":2008,"claim":"Confirmed the structural basis of AR transactivation and added PKD1 as a complex partner at the PSA promoter, refining how AR domain architecture and kinase partners tune transcription.","evidence":"Domain mutagenesis, reporter assays, Co-IP, ChIP at PSA promoter, siRNA","pmids":["18612376","18602367"],"confidence":"High","gaps":["PKD1 phosphorylation site on AR not mapped","How N/C interaction couples to specific coactivators not defined"]},{"year":2010,"claim":"Pinpointed CDK9-mediated S81 phosphorylation as the dominant hormone-induced AR modification controlling promoter selectivity and growth, establishing a direct kinase-to-transcription link.","evidence":"In vitro kinase assay with MS, mutagenesis (S81A), pharmacological inhibition, stable cell lines","pmids":["20980437"],"confidence":"High","gaps":["Downstream effectors of S81 phosphorylation incompletely defined","Whether S81 alters cofactor binding directly not shown"]},{"year":2014,"claim":"Showed MEIS1 directly represses AR by promoting NCoR/SMRT corepressor recruitment and modulating AR nuclear translocation, adding a corepressor-loading mechanism of AR control.","evidence":"Co-IP, GST pull-down, reporter assays, localization, ChIP at PSA promoter","pmids":["25158280"],"confidence":"Medium","gaps":["MEIS1 interaction domain on AR not mapped","Genome-wide impact on AR cistrome unknown"]},{"year":2016,"claim":"Extended AR function beyond prostate to ER+ breast cancer (required for maximal ER chromatin binding) and revealed cell-cycle-resolved expansion of the AR cistrome including pro-metastatic targets.","evidence":"ChIP-seq, anti-androgen inhibition, proliferation and xenograft assays; cell-cycle-phased ChIP-seq","pmids":["27565181","27669432"],"confidence":"Medium","gaps":["Mechanism of AR-ER chromatin cooperativity not resolved","How cell cycle phase redirects AR binding unclear"]},{"year":2017,"claim":"Resolved both protein-stability control (Aurora A→CHIP phosphorylation activating AR degradation) and direct N-terminal coactivator engagement (Vav3 DH domain) governing AR/AR-V7 activity.","evidence":"In vitro kinase assay, CHIP S273A mutagenesis, RNAi, ubiquitination assays; domain mutagenesis and Co-IP for Vav3","pmids":["28536143","28811363"],"confidence":"High","gaps":["Whether CHIP-mediated degradation operates on AR-V7 not addressed","Vav3 effect on full-length AR cistrome unmeasured"]},{"year":2018,"claim":"Defined AR membrane trafficking and additional ubiquitin-pathway control, showing KIF5B-driven microtubule transport activates HSP27 signaling and CNPY2 protects AR from MYLIP-mediated degradation.","evidence":"Co-IP, GST pull-down, microtubule disruption, KIF5B knockdown, fractionation; ubiquitination and E2/E3 interaction assays","pmids":["29934310","29707137"],"confidence":"Medium","gaps":["Functional output of membrane AR on specific genes not defined","Structural basis of MYLIP-AR recognition unknown"]},{"year":2020,"claim":"Uncovered KIF15-USP14 stabilization of AR/AR-V7 in a feedforward loop and DOT1L-marked enhancer control of AR/MYC, linking deubiquitination and chromatin marking to AR persistence.","evidence":"Co-IP, ubiquitination assays, ChIP for AR at KIF15 locus; ChIP-seq and DOT1L inhibition","pmids":["33277366","32814769"],"confidence":"Medium","gaps":["How KIF15 promotes USP14 recruitment mechanistically unresolved","Generality of DOT1L feedforward loop beyond MYC unknown"]},{"year":2021,"claim":"Connected AR to metabolic and non-canonical chromatin programs: direct ARE-driven SDHA/SDHB regulation with a succinate/HSP27 reactivation loop, and acquisition of ARE/FOXA1-independent binding sites in enzalutamide-resistant CRPC.","evidence":"ChIP at SDH AREs, enzyme/calcium assays, kinase inhibition; genome-wide ChIP-seq, RNA-seq, PDX models","pmids":["33709547","33750801"],"confidence":"High","gaps":["Determinants of non-canonical site selection incompletely defined","How succinate triggers calcium release mechanistically unclear"]},{"year":2022,"claim":"Established multi-layered post-transcriptional control of AR mRNA (m6A via METTL3/YTHDF2 and YTHDF3/G3BP1; m5C via NSUN2/YBX1), DUB-mediated stabilization (OTUD6A erasing K11 ubiquitin), and the EZH2 cryptic transactivation domain recruiting AR/AR-V7 to oncogenes.","evidence":"RNA m6A/m5C sequencing, RIP-qPCR, EMSA, polysome profiling, MS-based substrate ID, ubiquitin linkage analysis, ChIP-seq, PROTAC depletion","pmids":["36370857","36169095","34939643","35233061","36300627"],"confidence":"High","gaps":["Interplay between competing RNA modifications not integrated","Whether these mRNA controls operate in prostate vs cardiac contexts uniformly unknown"]},{"year":2023,"claim":"Showed AR differentially controls Hippo effectors (YAP translation vs WWTR1 transcription) via SRF, broadening AR's reach into growth-control crosstalk.","evidence":"Translational and transcriptional reporters, SRF manipulation, anchorage-independent growth assays","pmids":["37385752"],"confidence":"Medium","gaps":["Direct vs indirect AR control of YAP translation not separated","Physiological relevance in vivo untested"]},{"year":null,"claim":"How the diverse AR control layers — site-specific phosphorylation, ubiquitin/DUB balance, mRNA modification, membrane trafficking, and non-canonical cistrome reprogramming — are integrated into a unified regulatory logic across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking modification states to cistrome selection","Tissue-specific weighting of these mechanisms undefined","Structural basis of non-canonical chromatin binding unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,4,21,24,29,30,31]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[21,29,30,32]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,22,29]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2,22]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,21,29]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,24]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,19,20,12]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[15,16,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,10,30,31]}],"complexes":[],"partners":["EZH2","MEIS1","DAX-1","PAK6","PKD1","KIF5B","VAV3","OTUD6A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10275","full_name":"Androgen receptor","aliases":["Dihydrotestosterone receptor","Nuclear receptor subfamily 3 group C member 4"],"length_aa":920,"mass_kda":99.2,"function":"Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues (PubMed:19022849). 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selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) now fit into breast cancer treatment algorithms?","date":"2001","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11850229","citation_count":22,"is_preprint":false},{"pmid":"31616657","id":"PMC_31616657","title":"Non-nuclear AR Signaling in Prostate Cancer.","date":"2019","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31616657","citation_count":21,"is_preprint":false},{"pmid":"17166536","id":"PMC_17166536","title":"Hic-5/ARA55: a prostate stroma-specific AR coactivator.","date":"2006","source":"Steroids","url":"https://pubmed.ncbi.nlm.nih.gov/17166536","citation_count":21,"is_preprint":false},{"pmid":"29664547","id":"PMC_29664547","title":"HSD3B2, HSD17B1, HSD17B2, ESR1, ESR2 and AR expression in infertile women with endometriosis.","date":"2018","source":"Ginekologia 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The AR N-terminal domain recruits coactivators via mechanisms distinct from other steroid receptors, correlating with the low affinity of the ligand-binding domain for canonical LxxLL-bearing coactivators.\",\n      \"method\": \"Review of functional studies including domain mutagenesis, transactivation assays, coregulator interaction studies\",\n      \"journal\": \"Endocrine reviews\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — synthesis of multiple independent labs' biochemical and functional studies establishing core AR transcriptional mechanism\",\n      \"pmids\": [\"11943742\", \"17940184\", \"12612376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PAK6 (p21-activated kinase 6) was cloned as an AR-interacting protein; it binds in vitro to the hinge region between the AR DNA- and ligand-binding domains without requiring ligand. PAK6 kinase activity is stimulated by AR binding. PAK6 inhibits AR transcriptional activity in transient transfection assays with episomal and integrated reporters, and is primarily cytoplasmic.\",\n      \"method\": \"Yeast two-hybrid/mammalian one-hybrid, in vitro binding assay, transient transfection reporter assay, in vitro kinase assay, subcellular localization by epitope tagging\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays plus functional kinase and transcription assays in single lab\",\n      \"pmids\": [\"11773441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DAX-1 (NROB1) directly interacts with AR and potently inhibits ligand-dependent AR transcriptional activation as well as the AR N-terminal/C-terminal (N/C) domain interaction. The interaction involves the N-terminal repeat domain of DAX-1 and the C-terminal ligand-binding/activation domain of AR. DAX-1 can relocalize AR in both cytoplasm and nucleus, suggesting intracellular tethering contributes to inhibition.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, transactivation reporter assay, subcellular localization imaging\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated with pull-down and Co-IP, functional inhibition confirmed in transcription assays, single lab\",\n      \"pmids\": [\"11875111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"AR acts as a master regulator of G1-S phase progression in prostate cancer cells, inducing signals that promote G1 cyclin-dependent kinase (CDK) activity, leading to phosphorylation and inactivation of the retinoblastoma tumor suppressor (RB), thereby governing androgen-dependent proliferation.\",\n      \"method\": \"Cell cycle analysis, loss-of-function experiments, phosphorylation assays for RB in prostate cancer cell lines\",\n      \"journal\": \"Nuclear receptor signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection in cell lines by multiple groups, RB phosphorylation as defined readout\",\n      \"pmids\": [\"18301781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The AR ligand-binding domain has low intrinsic transactivation properties correlating with low affinity for canonical LxxLL-bearing coactivators; instead, AR transcriptional activation involves alternative recruitment of coactivators to the N-terminal domain and hinge region. A strong ligand-induced N-terminal/C-terminal (N/C) intramolecular interaction is involved in many aspects of AR function as a transcription factor.\",\n      \"method\": \"Domain mutagenesis, transactivation reporter assays, interaction studies with LxxLL coactivators\",\n      \"journal\": \"Nuclear receptor signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structure-function analysis with mutagenesis replicated across multiple labs\",\n      \"pmids\": [\"18612376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Protein kinase D1 (PKD1) forms a protein complex with AR in prostate cancer cells and is associated with the AR transcriptional complex at the PSA gene promoter. Both wild-type and kinase-dead PKD1 attenuate ligand-dependent AR transcriptional activation, while PKD1 knockdown enhances it.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP) at PSA promoter, transactivation reporter assay, siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus functional reporter assay, single lab\",\n      \"pmids\": [\"18602367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CDK9 phosphorylates AR at serine 81 (S81) in vitro and in cells; this is the highest stoichiometric phosphorylation on AR in response to hormone. CDK9 knockdown or pharmacological inhibition reduces S81 phosphorylation and AR transcriptional activity. Loss of S81 phosphorylation (S81A mutant) limits prostate cancer cell growth and alters AR promoter selectivity for endogenous target genes.\",\n      \"method\": \"In vitro kinase assay with mass spectrometry, siRNA knockdown, pharmacological inhibition (DRB, Flavopiridol), stable cell lines with wild-type vs. S81A mutant AR, endogenous target gene expression analysis\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus mutagenesis plus cellular validation with multiple inhibitor approaches in single rigorous study\",\n      \"pmids\": [\"20980437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Hic-5/ARA55 functions as a prostate stroma-specific AR coactivator; its expression influences androgen-induced keratinocyte growth factor (KGF) expression in WPMY-1 prostate stromal cells.\",\n      \"method\": \"Expression analysis in stromal vs. epithelial cells, functional transcription assay for KGF induction\",\n      \"journal\": \"Steroids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic follow-up reported in abstract\",\n      \"pmids\": [\"17166536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AR is required for maximum ER genomic binding in ER+/AR+ breast cancer cells; estradiol induces AR chromatin binding at sites enriched for estrogen response elements that overlap with ER-binding sites. AR inhibition (enzalutamide, MJC13) reduces baseline and estradiol-mediated proliferation and synergizes with tamoxifen and fulvestrant.\",\n      \"method\": \"ChIP-seq for AR chromatin binding, anti-androgen inhibition (enzalutamide/MJC13), cell proliferation assays, in vivo xenograft models\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus functional cell and in vivo studies in single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"27565181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AR membrane transport to the plasma membrane is microtubule-dependent and mediated by the motor protein KIF5B; disruption of KIF5B function interferes with AR membrane association. AR physically interacts with KIF5B, and androgen enhances this interaction. Membrane-associated AR activates HSP27, which mediates membrane-to-nuclear signal transduction to potentiate nuclear AR transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, microtubule disruption assays, KIF5B knockdown, subcellular fractionation, HSP27 functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and pull-down plus functional KIF5B knockdown and HSP27 pathway analysis, single lab\",\n      \"pmids\": [\"29934310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AKR1C3 increases AR-V7 protein stability in enzalutamide-resistant prostate cancer cells through activation of the ubiquitin-mediated proteasome pathway; indomethacin (AKR1C3 inhibitor) decreases AR/AR-V7 protein expression in vitro and in vivo via ubiquitin-proteasome pathway activation.\",\n      \"method\": \"Western blot protein stability assay, ubiquitin assay, pharmacological inhibition with indomethacin, in vivo xenograft model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic ubiquitination assays plus in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"31308078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Aurora kinase A (AURKA) phosphorylates the E3 ligase CHIP at S273, activating its E3 ligase activity toward AR. The 2-methoxyestradiol→Aurora A→CHIP→AR pathway promotes proteasomal degradation of AR; cells expressing CHIP S273A mutant show attenuated AR degradation, confirming this phosphorylation is required.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (CHIP S273A), AURKA inhibitors and RNAi knockdown, AR ubiquitination and degradation assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis validation plus RNAi and pharmacological confirmation, single rigorous study\",\n      \"pmids\": [\"28536143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KIF15 directly binds the N-terminus of AR/AR-V7 and prevents AR/AR-V7 protein degradation by increasing the association of deubiquitinase USP14 with AR/AR-V7; in turn, transcriptionally active AR stimulates KIF15 expression, forming a reciprocal activation loop.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assay, protein stability assay, ubiquitination assay, ChIP for AR at KIF15 locus\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for binding, functional ubiquitination assay, reciprocal transcriptional regulation confirmed, single lab\",\n      \"pmids\": [\"33277366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DOT1L histone methyltransferase marks a distal enhancer in the MYC gene with H3K79 methylation; this enhancer is bound by AR and DOT1L specifically in AR-positive prostate cancer cells. DOT1L inhibition reduces MYC expression, upregulates E3 ubiquitin ligases HECTD4 and MYCBP2, and promotes AR and MYC degradation in a negative feedforward loop.\",\n      \"method\": \"ChIP-seq, genetic and chemical inhibition of DOT1L, AR-positive vs. AR-negative cell comparison, ubiquitin ligase expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus genetic/chemical inhibition with mechanistic downstream pathway analysis, single lab\",\n      \"pmids\": [\"32814769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A cryptic transactivation domain of EZH2 (EZH2TAD) directly binds both AR and constitutively active AR splice variant AR-V7, mediating assembly and recruitment of transactivation-related machineries at genomic sites that lack PRC2 binding (non-canonical EZH2 function). EZH2TAD is required for chromatin recruitment of EZH2 to oncogenes and for EZH2-mediated oncogene activation in prostate cancer.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, domain mutagenesis, PROTAC depletion (MS177), in vitro and in vivo functional assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain binding characterization with Co-IP/mutagenesis, ChIP-seq, and in vivo validation in single rigorous study\",\n      \"pmids\": [\"36300627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL3 epigenetically represses AR expression in cardiac fibroblasts via m6A modification of AR mRNA in an m6A-YTHDF2-dependent manner; decreased AR expression activates HIF-1α signaling, enhancing glycolysis and cardiac fibroblast proliferation. AR interacts with HIF-1α and its overexpression reduces HIF-1α axis and inhibits glycolysis.\",\n      \"method\": \"RNA m6A sequencing, METTL3 knockdown/overexpression, Co-IP for AR-HIF-1α interaction, glycolysis assays, in vivo cardiac fibrosis model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A sequencing plus Co-IP plus gain/loss-of-function, single lab\",\n      \"pmids\": [\"36370857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NSUN2 posttranscriptionally stabilizes AR mRNA through cluster m5C modification in a m5C-YBX1-dependent manner; NSUN2 depletion decreases AR and AR-V7 expression and activity. AR transcriptionally regulates NSUN2, forming a positive feedback loop. YBX1 binds to AR m5C sites as confirmed by RIP-qPCR and EMSA.\",\n      \"method\": \"RNA bisulfite sequencing (RNA-BisSeq), in vitro enzyme reaction assay, RIP-qPCR, EMSA, ChIP, luciferase assay for AR binding to NSUN2 promoter\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic modification assay, RNA-BisSeq, and multiple binding assays, single lab\",\n      \"pmids\": [\"36169095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AR mRNA translation is coordinately regulated by RNA-binding proteins YTHDF3 and G3BP1: m6A-modified AR mRNA is bound by YTHDF3 and translationally stimulated under ambient conditions, while m6A-unmodified AR mRNA is bound by G3BP1 and translationally repressed. Under AR pathway inhibition stress, m6A-modified AR mRNA recruits to stress granules (SGs) where it undergoes liquid-liquid phase separation with YTHDF3, reducing translation.\",\n      \"method\": \"Polysome profiling, RNA-protein interaction assay, stress granule imaging, m6A sequencing, YTHDF3/G3BP1 silencing\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polysome and SG fractionation plus RNA-protein binding assays and m6A modification analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34939643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ENZ-resistant CRPC cells acquire non-canonical AR binding sites (ARBS-gained) lacking canonical androgen response elements (ARE) and FOXA1 motifs, which are enriched with CpG islands and binding sites for CXXC5 and TET2. ARBS-gained loci are enriched with H3K27ac, and ENZ-resistant cells are hypersensitive to BET/CBP-p300 dual inhibition.\",\n      \"method\": \"Genome-wide ChIP-seq, RNA-seq, patient-derived xenografts, pharmacological inhibition with NEO2734\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and RNA-seq with PDX validation, single lab\",\n      \"pmids\": [\"33750801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OTUD6A deubiquitinase stabilizes AR by erasing K11-linked polyubiquitination of AR; catalytically inactive OTUD6A mutant fails to stabilize AR. OTUD6A also stabilizes Brg1 (SWI/SNF ATPase subunit) by erasing K27-linked polyubiquitination.\",\n      \"method\": \"Mass spectrometry substrate identification, Co-immunoprecipitation, ubiquitination assays with linkage-specific analysis, catalytically inactive mutant, in vivo xenograft models\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-based substrate identification, specific ubiquitin linkage characterization, mutagenesis, and in vivo validation in single rigorous study\",\n      \"pmids\": [\"35233061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CNPY2 controls AR protein levels by inhibiting MYLIP (an E3 ubiquitin ligase)-mediated AR ubiquitination and proteasomal degradation; CNPY2 decreases MYLIP ubiquitination activity by inhibiting the interaction between MYLIP and E2 ubiquitin ligase UBE2D1.\",\n      \"method\": \"Ubiquitination assay, Co-immunoprecipitation, CNPY2 knockdown/overexpression, proteasome inhibitor treatment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic ubiquitination pathway dissection with Co-IP and E2/E3 interaction assays, single lab\",\n      \"pmids\": [\"29707137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AR directly regulates transcription of succinate dehydrogenase catalytic subunit genes (SDHA, SDHB) via androgen response elements (AREs). AR pathway inhibition suppresses SDH activity, causing succinate accumulation; succinate triggers calcium release, which phospho-activates HSP27 via CaMKK2/AMPK/p38 axis, stabilizing and reactivating AR protein.\",\n      \"method\": \"ChIP for AR at SDHA/SDHB AREs, SDH enzyme activity assay, calcium imaging, pharmacological kinase inhibition, AR protein stability assay, tissue microarray validation\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct ChIP evidence for AR-ARE interaction, biochemical pathway dissection with enzymatic assays and kinase inhibition, tissue validation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"33709547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MEIS1 homeodomain transcription factor directly interacts with AR (identified by Co-IP and GST pull-down) and inhibits AR transcriptional activity, reduces AR target gene expression, modulates AR cytoplasm/nucleus translocation, and promotes recruitment of corepressors NCoR and SMRT to the AR complex in the presence of androgen.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, transactivation reporter assay, subcellular localization assay, ChIP for AR at PSA promoter\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays plus multiple functional assays including ChIP, single lab\",\n      \"pmids\": [\"25158280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DUSP22 interacts with AR as a regulatory partner, dephosphorylates AR at Tyr534 to interfere with EGF-induced AR phosphorylation, and suppresses PSA gene expression through phosphatase-dependent pathways. DUSP22 also dephosphorylates EGFR and its downstream ERK1/2 signaling.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay (Tyr534 AR), DUSP22 overexpression/loss-of-function, PSA reporter assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus site-specific phosphorylation assay plus functional reporter, single lab\",\n      \"pmids\": [\"31693867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AR has an expanded repertoire of transcriptional targets in actively cycling prostate cancer cells, segregating into cell-cycle-common and phase-restricted AR functions. AR regulates dihydroceramide desaturase 1 specifically in mitotically active cells, promoting pro-metastatic phenotypes.\",\n      \"method\": \"AR ChIP-seq as a function of cell cycle phase, gene expression profiling, functional assays for pro-metastatic phenotypes\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell cycle-resolved ChIP-seq plus functional validation, single lab\",\n      \"pmids\": [\"27669432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AR-EZH2 protein interaction is impaired by pre-castration androgen levels but recovered by post-castration androgen levels; AR overexpression alone with low androgen can rapidly redistribute AR chromatin binding and activate a distinct transcription program enriched for DNA damage repair pathways, with EZH2 involvement in this reprogramming.\",\n      \"method\": \"Co-IP for AR-EZH2 interaction, inducible AR overexpression model, ChIP-seq cistrome analysis, RNA-seq, bioinformatic prediction\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with androgen-level modulation plus ChIP-seq and RNA-seq, single lab\",\n      \"pmids\": [\"36408179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AR activates YAP translation and induces transcription of the TAZ-encoding gene WWTR1 in prostate cancer, differentially regulating these two Hippo pathway effectors. AR-mediated YAP/TAZ activation is regulated by the RhoA transcriptional mediator SRF. YAP/TAZ are not essential for sustaining AR activity.\",\n      \"method\": \"Androgen stimulation, AR inhibition, translational reporter assay, transcription assay, SRF manipulation, anchorage-independent growth assays\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — translational vs. transcriptional distinction established experimentally, SRF pathway validated, single lab\",\n      \"pmids\": [\"37385752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Vav3 DH domain directly interacts with the N-terminal region of AR-V7 (and full-length AR); Vav3 DH domain expression disrupts Vav3-AR-V7 interaction and inhibits Vav3 enhancement of AR-V7 activity, also disrupting AR-V7 interaction with coactivators SRC1 and Vav2. Disruption of AR-V7/coactivator interaction decreases AR-V7 nuclear levels.\",\n      \"method\": \"Mutational and biochemical domain interaction studies, Co-IP, transcriptional reporter assays, functional cell proliferation and anchorage-independent growth assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis plus biochemical binding plus multiple functional readouts, single lab\",\n      \"pmids\": [\"28811363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ACK1 (oncogenic tyrosine kinase) phosphorylates histone H4, leading to epigenetic upregulation of AR expression as a mechanism of castration-resistant prostate cancer resistance to anti-androgens.\",\n      \"method\": \"Kinase assay, chromatin analysis of H4 phosphorylation at AR locus, ACK1-selective inhibitor (R)-9b\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic detail available in abstract\",\n      \"pmids\": [\"32885168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AR-V7 and full-length AR display distinct cistromes with numerous differential chromatin binding sites in prostate cancer cells; AR-V7 preferential binding sites are enriched for a half-ARE de novo motif and are located proximal to transcription start sites, without FOXA1 enrichment, distinguishing them from canonical half-ARE AR-V7 sites.\",\n      \"method\": \"ChIP-seq for AR and AR-V7 at matched expression levels in LNCaP and VCaP cells, de novo motif analysis, RNA-seq transcriptome comparison\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — controlled ChIP-seq with matched receptor levels plus RNA-seq, single lab\",\n      \"pmids\": [\"35354884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AR binds to androgen response elements (AREs) in the miR-145 promoter and suppresses p53-induced miR-145 expression; decreased miR-145 leads to upregulation of HIF2α/VEGF/MMP9/CCND1 in renal cell carcinoma, promoting tumor progression independent of VHL status.\",\n      \"method\": \"ChIP for AR at miR-145 promoter ARE, luciferase reporter assay, AR-shRNA knockdown, miR-145 mimic rescue, orthotopic xenograft mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter plus in vivo rescue experiment, single lab\",\n      \"pmids\": [\"26304926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AR directly regulates HCC cell migration and invasion via a miR-325/ACP5 signaling axis; AR transcriptionally regulates miR-325, which directly targets the 3'UTR of ACP5 mRNA to suppress its translation and reduce cell migration/invasion.\",\n      \"method\": \"AR knockdown, miR-325 overexpression, 3'UTR luciferase reporter assay for ACP5, in vivo orthotopic xenograft model\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR reporter validates direct miRNA-target interaction, AR transcriptional regulation plus in vivo validation, single lab\",\n      \"pmids\": [\"33753989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CpG methylation of the proximal AR promoter inversely correlates with AR mRNA expression; a 158-bp region containing two consecutive CpGs is sufficient to suppress reporter gene expression when methylated. RUNX1 binds this region and ectopic RUNX1 expression inhibits reporter gene expression through this region, identifying it as a regulator of AR transcription.\",\n      \"method\": \"Bisulfite sequencing of AR promoter, luciferase reporter assay with methylated template, RUNX1 ChIP and ectopic expression in HEK293T cells\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — methylation-reporter mechanistic assay plus RUNX1 binding and functional validation, single lab\",\n      \"pmids\": [\"30124873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sex-associated expression analysis in lungs showed that ACE2 and AR expression are sexually dimorphic and higher in males; ACE2 expression is moderately suppressible by enzalutamide (AR antagonist) in male mice. TMPRSS2 expression in lungs was not increased in males vs. females and was not decreased by enzalutamide treatment (negative result for TMPRSS2-AR regulation in lung).\",\n      \"method\": \"Comparative gene expression in human and mouse lungs, pharmacological AR antagonism with enzalutamide in male mice\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, expression analysis with pharmacological intervention but limited mechanistic mechanistic follow-up\",\n      \"pmids\": [\"33083800\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"AR (androgen receptor, NR3C4) is a ligand-activated nuclear transcription factor that, upon androgen binding, undergoes a conformational change involving a strong N-terminal/C-terminal intramolecular interaction, translocates to the nucleus (via microtubule/KIF5B-dependent membrane-associated intermediate), binds androgen response elements (AREs) or non-canonical chromatin sites, and recruits diverse coactivators (including through its N-terminal domain rather than canonical LxxLL surfaces) and corepressors to regulate target gene transcription; its activity is modulated by phosphorylation (CDK9 at S81, EGFR-induced Tyr534), ubiquitin-mediated proteasomal degradation (via E3 ligases MYLIP, CHIP, and deubiquitinases USP14, USP22, OTUD6A), m6A/m5C mRNA modification (METTL3/YTHDF2 and NSUN2/YBX1), direct binding of coregulators (PAK6, DAX-1, PKD1, MEIS1, Hic-5/ARA55, EZH2TAD, Vav3, DOT1L), and directly drives G1-S cell cycle progression via CDK activation and RB phosphorylation in prostate cancer; AR also directly regulates metabolic gene expression including succinate dehydrogenase subunits, and non-genomically activates HSP27 at the membrane to potentiate nuclear transcriptional activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AR (NR3C4) is a ligand-activated nuclear transcription factor that governs androgen-dependent gene expression programs, most prominently driving G1-S cell cycle progression in prostate cancer through induction of G1 cyclin-dependent kinase activity and inactivating phosphorylation of RB [#0, #3]. Unlike other steroid receptors, AR's ligand-binding domain has weak intrinsic transactivation and low affinity for canonical LxxLL coactivators; productive transcription instead depends on a strong ligand-induced N-terminal/C-terminal intramolecular interaction and on coactivator recruitment to the N-terminal domain and hinge region [#0, #4]. AR binds androgen response elements as well as non-canonical chromatin sites — including ENZ-resistance-associated sites lacking AREs and FOXA1 motifs and distinct AR-V7 cistromes enriched for half-ARE motifs — to direct context-specific transcriptional outputs [#18, #29]. AR target genes extend to metabolic regulators such as succinate dehydrogenase subunits SDHA/SDHB, whose suppression triggers a succinate/calcium/HSP27 feedback loop that reactivates AR protein [#21], and to microRNA-mediated programs (miR-145, miR-325) controlling tumor progression in renal and hepatocellular carcinoma [#30, #31]. AR activity is shaped by phosphorylation (CDK9 at S81, which sets the highest-stoichiometry hormone-induced phosphorylation and controls promoter selectivity [#6]; reversal of EGF-induced Tyr534 phosphorylation by DUSP22 [#23]) and by direct coregulator binding, including the kinase PKD1 [#5], homeodomain factor MEIS1 which recruits NCoR/SMRT corepressors [#22], and a cryptic EZH2 transactivation domain that recruits AR and AR-V7 to oncogenes independent of PRC2 [#14]. AR protein abundance is set by a network of E3 ligases and deubiquitinases: CHIP activated by Aurora A phosphorylation and MYLIP (counteracted by CNPY2) drive degradation, while OTUD6A (erasing K11-linked ubiquitin) and USP14 (recruited via KIF15) stabilize AR and AR-V7 [#11, #19, #20, #12]. AR also undergoes membrane-associated, microtubule/KIF5B-dependent trafficking that activates HSP27 to potentiate nuclear transcription [#9], and its mRNA is post-transcriptionally controlled by m6A (METTL3/YTHDF2, YTHDF3/G3BP1) and m5C (NSUN2/YBX1) modifications [#15, #16, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that AR is a ligand-activated transcription factor with a non-canonical coactivator-recruitment mechanism, explaining why its weak ligand-binding domain depends on the N-terminal domain for transactivation.\",\n      \"evidence\": \"Synthesis of domain mutagenesis, transactivation, and coregulator interaction studies\",\n      \"pmids\": [\"11943742\", \"17940184\", \"12612376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which coactivator surfaces engage the N-terminal domain\", \"Mechanism of ligand selectivity by coregulators not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified PAK6 and DAX-1 as direct AR-interacting inhibitors, showing AR transcriptional output is restrained by partners acting through the hinge and the N/C interaction respectively.\",\n      \"evidence\": \"Yeast/mammalian two-hybrid, GST pull-down, Co-IP, kinase and reporter assays\",\n      \"pmids\": [\"11773441\", \"11875111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PAK6 kinase substrate on AR not identified\", \"Physiological significance of DAX-1 tethering in vivo unestablished\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined AR as a master regulator of G1-S progression, linking androgen signaling to CDK-mediated RB inactivation and androgen-dependent proliferation.\",\n      \"evidence\": \"Cell cycle analysis, loss-of-function, RB phosphorylation assays in prostate cancer lines\",\n      \"pmids\": [\"18301781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AR target genes mediating CDK activation not fully enumerated\", \"Connection to specific cyclins unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Confirmed the structural basis of AR transactivation and added PKD1 as a complex partner at the PSA promoter, refining how AR domain architecture and kinase partners tune transcription.\",\n      \"evidence\": \"Domain mutagenesis, reporter assays, Co-IP, ChIP at PSA promoter, siRNA\",\n      \"pmids\": [\"18612376\", \"18602367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PKD1 phosphorylation site on AR not mapped\", \"How N/C interaction couples to specific coactivators not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Pinpointed CDK9-mediated S81 phosphorylation as the dominant hormone-induced AR modification controlling promoter selectivity and growth, establishing a direct kinase-to-transcription link.\",\n      \"evidence\": \"In vitro kinase assay with MS, mutagenesis (S81A), pharmacological inhibition, stable cell lines\",\n      \"pmids\": [\"20980437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of S81 phosphorylation incompletely defined\", \"Whether S81 alters cofactor binding directly not shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed MEIS1 directly represses AR by promoting NCoR/SMRT corepressor recruitment and modulating AR nuclear translocation, adding a corepressor-loading mechanism of AR control.\",\n      \"evidence\": \"Co-IP, GST pull-down, reporter assays, localization, ChIP at PSA promoter\",\n      \"pmids\": [\"25158280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MEIS1 interaction domain on AR not mapped\", \"Genome-wide impact on AR cistrome unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended AR function beyond prostate to ER+ breast cancer (required for maximal ER chromatin binding) and revealed cell-cycle-resolved expansion of the AR cistrome including pro-metastatic targets.\",\n      \"evidence\": \"ChIP-seq, anti-androgen inhibition, proliferation and xenograft assays; cell-cycle-phased ChIP-seq\",\n      \"pmids\": [\"27565181\", \"27669432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of AR-ER chromatin cooperativity not resolved\", \"How cell cycle phase redirects AR binding unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved both protein-stability control (Aurora A→CHIP phosphorylation activating AR degradation) and direct N-terminal coactivator engagement (Vav3 DH domain) governing AR/AR-V7 activity.\",\n      \"evidence\": \"In vitro kinase assay, CHIP S273A mutagenesis, RNAi, ubiquitination assays; domain mutagenesis and Co-IP for Vav3\",\n      \"pmids\": [\"28536143\", \"28811363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CHIP-mediated degradation operates on AR-V7 not addressed\", \"Vav3 effect on full-length AR cistrome unmeasured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined AR membrane trafficking and additional ubiquitin-pathway control, showing KIF5B-driven microtubule transport activates HSP27 signaling and CNPY2 protects AR from MYLIP-mediated degradation.\",\n      \"evidence\": \"Co-IP, GST pull-down, microtubule disruption, KIF5B knockdown, fractionation; ubiquitination and E2/E3 interaction assays\",\n      \"pmids\": [\"29934310\", \"29707137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of membrane AR on specific genes not defined\", \"Structural basis of MYLIP-AR recognition unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncovered KIF15-USP14 stabilization of AR/AR-V7 in a feedforward loop and DOT1L-marked enhancer control of AR/MYC, linking deubiquitination and chromatin marking to AR persistence.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, ChIP for AR at KIF15 locus; ChIP-seq and DOT1L inhibition\",\n      \"pmids\": [\"33277366\", \"32814769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How KIF15 promotes USP14 recruitment mechanistically unresolved\", \"Generality of DOT1L feedforward loop beyond MYC unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected AR to metabolic and non-canonical chromatin programs: direct ARE-driven SDHA/SDHB regulation with a succinate/HSP27 reactivation loop, and acquisition of ARE/FOXA1-independent binding sites in enzalutamide-resistant CRPC.\",\n      \"evidence\": \"ChIP at SDH AREs, enzyme/calcium assays, kinase inhibition; genome-wide ChIP-seq, RNA-seq, PDX models\",\n      \"pmids\": [\"33709547\", \"33750801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of non-canonical site selection incompletely defined\", \"How succinate triggers calcium release mechanistically unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established multi-layered post-transcriptional control of AR mRNA (m6A via METTL3/YTHDF2 and YTHDF3/G3BP1; m5C via NSUN2/YBX1), DUB-mediated stabilization (OTUD6A erasing K11 ubiquitin), and the EZH2 cryptic transactivation domain recruiting AR/AR-V7 to oncogenes.\",\n      \"evidence\": \"RNA m6A/m5C sequencing, RIP-qPCR, EMSA, polysome profiling, MS-based substrate ID, ubiquitin linkage analysis, ChIP-seq, PROTAC depletion\",\n      \"pmids\": [\"36370857\", \"36169095\", \"34939643\", \"35233061\", \"36300627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between competing RNA modifications not integrated\", \"Whether these mRNA controls operate in prostate vs cardiac contexts uniformly unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed AR differentially controls Hippo effectors (YAP translation vs WWTR1 transcription) via SRF, broadening AR's reach into growth-control crosstalk.\",\n      \"evidence\": \"Translational and transcriptional reporters, SRF manipulation, anchorage-independent growth assays\",\n      \"pmids\": [\"37385752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect AR control of YAP translation not separated\", \"Physiological relevance in vivo untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse AR control layers — site-specific phosphorylation, ubiquitin/DUB balance, mRNA modification, membrane trafficking, and non-canonical cistrome reprogramming — are integrated into a unified regulatory logic across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking modification states to cistrome selection\", \"Tissue-specific weighting of these mechanisms undefined\", \"Structural basis of non-canonical chromatin binding unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 4, 21, 24, 29, 30, 31]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [21, 29, 30, 32]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 22, 29]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2, 22]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 21, 29]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 24]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 19, 20, 12]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [15, 16, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 10, 30, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EZH2\", \"MEIS1\", \"DAX-1\", \"PAK6\", \"PKD1\", \"KIF5B\", \"Vav3\", \"OTUD6A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"AR","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"rich","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 12612376"},"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}