{"gene":"KDM5D","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1995,"finding":"KDM5D (SMCY) encodes an 11-residue peptide epitope that is presented by HLA-B7 as a human H-Y minor histocompatibility antigen; the homologous X-chromosome protein SMCX differs by two amino acid residues in the same region, explaining male specificity.","method":"Peptide elution from HLA molecules, mass spectrometry, T-cell cytotoxicity assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical identification of the peptide by mass spectrometry combined with functional T-cell assay, replicated in two independent papers (PMID:7667640 and PMID:7544442)","pmids":["7667640"],"is_preprint":false},{"year":1995,"finding":"The mouse Smcy gene encodes the H-Y Kk epitope defined by the octamer peptide TENSGKDI; no equivalent peptide is found in the X-homologue Smcx, establishing Smcy (KDM5D ortholog) as a source of male-specific transplantation antigen peptides.","method":"Peptide identification, T-cell cytotoxicity assay, gene mapping","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — peptide identified biochemically, functional T-cell recognition confirmed, independent replication across mouse and human systems","pmids":["7544442"],"is_preprint":false},{"year":2008,"finding":"SMCY (KDM5D) forms a distinct protein complex with MSH5 (a meiosis-regulatory protein) in human testicular germ cells (NEC8 line), co-localizes with MSH5 at a specific stage of meiotic prophase during murine spermatogenesis, and displays histone H3K4 demethylase activity in biochemical assays.","method":"Co-immunoprecipitation/biochemical protein identification, histone demethylase activity assay, immunohistochemistry, co-localization","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with demethylase activity assay and co-localization, single lab with two orthogonal methods","pmids":["18459961"],"is_preprint":false},{"year":2016,"finding":"KDM5D physically interacts with the androgen receptor (AR) in the nucleus and regulates AR transcriptional activity by demethylating H3K4me3 marks; knockdown of KDM5D dysregulates AR signaling and confers docetaxel resistance in prostate cancer cells in the presence of dihydrotestosterone.","method":"Co-immunoprecipitation (nuclear fraction), RNA-seq, ChIP, siRNA knockdown, cell viability assay","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating physical interaction, ChIP showing H3K4me3 changes at AR target genes, functional rescue experiments, multiple orthogonal methods in one study","pmids":["27185910"],"is_preprint":false},{"year":2018,"finding":"KDM5D preferentially binds to promoter regions enriched for cell-cycle transcription factor motifs (by ChIP-seq); loss of KDM5D leads to dysregulated H3K4me3 marks, accelerated cell cycle progression and mitotic entry, increased DNA-replication stress, and activation of ATR kinase; ATR inhibition in KDM5D-deficient prostate cancer cells enhances DNA damage and induces apoptosis.","method":"ChIP-seq, FISH (Y chromosome deletion), siRNA/shRNA knockdown, ATR inhibitor treatment, apoptosis assay","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq with functional loss-of-function, mechanistic epistasis with ATR pathway, multiple orthogonal methods in a single rigorous study","pmids":["29863497"],"is_preprint":false},{"year":2019,"finding":"KDM5D demethylates H3K4me3 at the promoter of CUL4A, reducing CUL4A expression, which leads to decreased ZEB1 and altered p21/p53 levels; knockdown of KDM5D in gastric cancer cells increases cell migration, invasion, and tumor formation in vivo, while overexpression suppresses epithelial-mesenchymal transition.","method":"ChIP-qPCR (H3K4me3 at CUL4A promoter), siRNA knockdown, transwell migration/invasion assay, in vivo xenograft","journal":"Journal of Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing demethylation at specific promoter with functional downstream consequences, single lab with multiple methods","pmids":["30864186"],"is_preprint":false},{"year":2019,"finding":"KDM5D knockdown via siRNA in cardiomyocyte differentiation models causes accumulation of cells in S-phase, impaired progression to cardiomyocytes, absence of spontaneous beating, and altered cardiac progenitor marker expression; KDM5D is upregulated during cardiac mesoderm stage of development and acts cooperatively with its X-homologue KDM5C.","method":"siRNA knockdown, cell cycle analysis (S-phase accumulation), expression profiling of cardiac progenitor markers, beating cell assay","journal":"Journal of Proteome Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular phenotype readout, single lab, multiple orthogonal methods","pmids":["31560558"],"is_preprint":false},{"year":2020,"finding":"Combined genetic deletion of Kdm5c and Kdm5d (but not either alone) in mice results in noncompaction cardiomyopathy with prominent trabecular extension and thin compacted myocardium, demonstrating that Kdm5d and Kdm5c have conserved and partially redundant roles in heart development.","method":"Genetic mouse knockouts (compound hemizygous and homozygous), histological examination of cardiac phenotype","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined cardiac phenotype, epistasis between X and Y paralogs established, single lab","pmids":["32081420"],"is_preprint":false},{"year":2021,"finding":"KDM5D suppresses E2F1 expression by mediating H3K4me3 demethylation at the E2F1 locus; reduced E2F1 in turn decreases transcription of FKBP4 (confirmed by ChIP-qPCR and luciferase reporter assays); overexpression of FKBP4 rescues the anti-tumor effect of KDM5D in colorectal cancer cells.","method":"ChIP-qPCR (H3K4me3 at E2F1 promoter), luciferase reporter assay, overexpression/rescue experiments, in vitro and in vivo growth/metastasis assays","journal":"Biochemical Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR plus reporter assay plus rescue experiment defining a KDM5D→E2F1→FKBP4 pathway, single lab","pmids":["34688635"],"is_preprint":false},{"year":2021,"finding":"miR-4661-5p targets KDM5D mRNA and downregulates KDM5D expression, leading to increased H3K4me3 at the Mars2 promoter and elevated Mars2 transcription, which promotes gastric cancer cell proliferation, migration, and invasion; direct KDM5D occupancy at the Mars2 promoter was demonstrated by ChIP.","method":"miRNA overexpression/inhibition, ChIP (H3K4me3 at Mars2 promoter), siRNA KDM5D knockdown, cell functional assays","journal":"Cell Biology International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at specific target locus with functional rescue, single lab","pmids":["34273914"],"is_preprint":false},{"year":2023,"finding":"In colorectal cancer, KRAS*-mediated activation of the STAT4 transcription factor drives transcriptional upregulation of KDM5D; KDM5D-dependent H3K4 demethylation represses regulators of epithelial tight junctions and MHC class I components; Kdm5d deletion increases tight junction integrity, decreases cell invasiveness, and enhances CD8+ T-cell-mediated cancer cell killing, while Kdm5d transgenic expression increases tumor invasiveness in vivo.","method":"Transgenic/conditional knockout mouse models, transcriptomic and chromatin mark analysis (ChIP-seq inferred), CD8+ T-cell killing assay, in vivo tumor invasion assay, STAT4 pathway analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple complementary genetic gain- and loss-of-function models in vivo, integrated molecular and functional readouts, cross-species validation, published in high-tier journal with rigorous controls","pmids":["37344599"],"is_preprint":false},{"year":2024,"finding":"KDM5D directly interacts with p38α (MAPK14) and demethylates p38α at lysine 165 (K165); K165 methylation promotes p38α phosphorylation and activation, while KDM5D-mediated demethylation inhibits p38α phosphorylation, thereby suppressing tumor cell proliferation and migration in non-small cell lung cancer xenograft models.","method":"Co-immunoprecipitation (KDM5D–p38α interaction), in vitro demethylation assay, site-directed mutagenesis (K165), phosphorylation assays, KDM5D knockdown/overexpression, xenograft tumor model","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro demethylation assay with mutagenesis (K165) plus Co-IP, phosphorylation mechanistic readout, in vivo tumor model; multiple orthogonal methods in a single rigorous study","pmids":["39636854"],"is_preprint":false},{"year":2024,"finding":"Curcumin enhances both the expression and demethylase activity of KDM5D (JARID1D), and increased KDM5D activity suppresses AR and EMT signaling cascades to inhibit invasion of castration-resistant prostate cancer cells.","method":"KDM5D overexpression/pharmacological activation by curcumin, demethylase activity assay, invasion assay, AR and EMT marker analysis","journal":"Cancer Cell International","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological activation without direct mutagenesis of KDM5D catalytic site; mechanism inferred from correlative activity and expression changes","pmids":["39218854"],"is_preprint":false},{"year":2023,"finding":"KDM5D upregulation promotes platinum (cisplatin) tolerance in head and neck squamous cell carcinoma by modulating Aurora Kinase B (AURKB) mRNA levels; KDM5D knockdown reduces persister-cell tolerance to platinum agents, causes DNA damage checkpoint deregulation and abnormal mitosis; AURKB inhibition overcomes the tolerance, identifying a KDM5D/AURKB regulatory axis.","method":"KDM5D knockdown (siRNA/shRNA), RT-qPCR (AURKB mRNA), cell cycle analysis, in vitro and in vivo (xenograft) drug tolerance assays","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular (AURKB mRNA) and cellular (mitotic catastrophe) phenotype, in vivo validation, single lab","pmids":["36982384"],"is_preprint":false}],"current_model":"KDM5D (SMCY/JARID1D) is a Y-chromosome-encoded histone H3K4 demethylase that removes methyl marks from H3K4me3 at gene promoters to regulate transcription; it physically interacts with the androgen receptor (in the nucleus) and with p38α (in the cytoplasm), demethylating p38α at K165 to suppress its phosphorylation and activity; it also forms a spermatogenesis-specific complex with the meiotic regulator MSH5; downstream, KDM5D suppresses E2F1, CUL4A, FKBP4, Mars2, and MHC-I/tight-junction gene programs, and its loss accelerates cell-cycle progression, increases DNA-replication stress with ATR activation, promotes epithelial-mesenchymal transition, and drives tumor invasiveness, while its gain-of-function suppresses these oncogenic phenotypes."},"narrative":{"mechanistic_narrative":"KDM5D (SMCY/JARID1D) is a Y-chromosome-encoded histone H3K4 demethylase that shapes transcriptional programs governing cell-cycle progression, genome stability, and tumor invasiveness [PMID:29863497, PMID:37344599]. Through removal of activating H3K4me3 marks at target promoters, it represses gene programs including E2F1 (and its downstream effector FKBP4), CUL4A, Mars2, and regulators of epithelial tight junctions and MHC class I [PMID:30864186, PMID:34688635, PMID:34273914, PMID:37344599]; loss of KDM5D accelerates cell-cycle progression and mitotic entry, increases DNA-replication stress with ATR activation, and promotes epithelial-mesenchymal transition and invasiveness, whereas its activity suppresses these phenotypes [PMID:29863497, PMID:30864186, PMID:37344599]. KDM5D was originally identified as the source of male-specific H-Y minor histocompatibility antigen peptides presented by MHC, distinguishing it from its X-homologue [PMID:7667640, PMID:7544442]. Beyond chromatin, KDM5D acts as a protein-lysine demethylase: it binds p38α (MAPK14) and demethylates it at K165 to suppress p38α phosphorylation and activity [PMID:39636854], and it physically associates with the androgen receptor in the nucleus to modulate AR transcriptional output, with its loss conferring docetaxel resistance in prostate cancer [PMID:27185910]. In germ cells, KDM5D forms a complex with the meiotic regulator MSH5 during spermatogenesis [PMID:18459961]. It cooperates with its X-paralog KDM5C in heart development [PMID:31560558, PMID:32081420]. Pharmacologically, its activity is regulated upstream by miR-4661-5p and by KRAS*/STAT4 signaling [PMID:34273914, PMID:37344599].","teleology":[{"year":1995,"claim":"Established KDM5D/SMCY as the molecular source of the male-specific H-Y minor histocompatibility antigen, explaining sex-mismatched transplant rejection at the level of a defined peptide epitope.","evidence":"Peptide elution from HLA molecules with mass spectrometry and T-cell cytotoxicity assays, in human (HLA-B7) and mouse (Kk) systems","pmids":["7667640","7544442"],"confidence":"High","gaps":["Did not address the enzymatic or chromatin function of the protein","Antigen presentation does not establish a cellular role for KDM5D"]},{"year":2008,"claim":"Showed that the SMCY protein possesses intrinsic histone H3K4 demethylase activity and physically partners with the meiotic regulator MSH5 in germ cells, assigning it a chromatin-modifying enzyme function and a spermatogenesis-specific complex.","evidence":"Reciprocal Co-IP, in vitro histone demethylase assay, and immunohistochemical co-localization during murine meiotic prophase","pmids":["18459961"],"confidence":"Medium","gaps":["Functional consequence of the MSH5 complex in meiosis not defined","Genome-wide demethylase targets not mapped","Single-lab finding"]},{"year":2016,"claim":"Connected KDM5D demethylase activity to androgen receptor signaling, linking its loss to therapy resistance in prostate cancer.","evidence":"Nuclear-fraction Co-IP, ChIP for H3K4me3 at AR targets, RNA-seq, siRNA knockdown, and docetaxel viability assays in prostate cancer cells","pmids":["27185910"],"confidence":"High","gaps":["Direct AR-binding interface not mapped","Whether AR regulation requires catalytic activity not isolated"]},{"year":2018,"claim":"Defined KDM5D as a genome-wide guardian of cell-cycle and replication control, showing its loss creates ATR-dependent replication stress that can be exploited therapeutically.","evidence":"ChIP-seq mapping to cell-cycle TF-motif promoters, loss-of-function knockdown, ATR inhibitor treatment, and apoptosis assays in prostate cancer cells","pmids":["29863497"],"confidence":"High","gaps":["Specific direct target genes mediating the replication-stress phenotype not individually validated","Catalytic dependence of phenotype not formally separated"]},{"year":2019,"claim":"Extended KDM5D function to suppression of EMT and invasion via promoter-specific H3K4me3 demethylation of CUL4A in gastric cancer.","evidence":"ChIP-qPCR at CUL4A promoter, siRNA knockdown, transwell migration/invasion assays, and xenografts","pmids":["30864186"],"confidence":"Medium","gaps":["Downstream ZEB1/p21/p53 effects correlative","Single-lab finding"]},{"year":2019,"claim":"Implicated KDM5D, cooperatively with its X-paralog KDM5C, in cardiac differentiation and cell-cycle control during development.","evidence":"siRNA knockdown in cardiomyocyte differentiation models with cell-cycle analysis and cardiac marker profiling (2019); compound Kdm5c/Kdm5d mouse knockouts with cardiac histology (2020)","pmids":["31560558","32081420"],"confidence":"Medium","gaps":["Molecular targets in cardiac tissue not identified","Degree of paralog redundancy versus distinct function not fully resolved"]},{"year":2021,"claim":"Mapped specific KDM5D-controlled oncogenic transcriptional axes, defining a KDM5D→E2F1→FKBP4 cascade and direct repression of Mars2, the latter relieved by miR-4661-5p.","evidence":"ChIP-qPCR at E2F1 and Mars2 promoters, luciferase reporters, miRNA over/under-expression, and rescue experiments in colorectal and gastric cancer cells","pmids":["34688635","34273914"],"confidence":"Medium","gaps":["Individual axes characterized in single cancer models","Whether axes operate concurrently in the same cells not tested"]},{"year":2023,"claim":"Placed KDM5D downstream of KRAS*/STAT4 signaling as an immune-evasion and invasion driver that represses tight-junction and MHC-I genes, with gain- and loss-of-function reversing CD8+ T-cell killing and invasiveness.","evidence":"Transgenic and conditional Kdm5d mouse models, transcriptomic/chromatin analysis, CD8+ T-cell killing assays, and in vivo invasion assays in colorectal cancer","pmids":["37344599"],"confidence":"High","gaps":["Direct chromatin occupancy at each repressed locus not individually resolved","Generalizability beyond KRAS-mutant context unknown"]},{"year":2023,"claim":"Identified a context-dependent role in which KDM5D upregulation promotes platinum tolerance through AURKB regulation in head and neck cancer, contrasting with its tumor-suppressive roles elsewhere.","evidence":"Knockdown, RT-qPCR for AURKB, cell-cycle analysis, AURKB inhibition, and in vivo drug-tolerance assays","pmids":["36982384"],"confidence":"Medium","gaps":["Mechanism of AURKB mRNA regulation (direct vs indirect) not resolved","Single-lab finding"]},{"year":2024,"claim":"Demonstrated that KDM5D is a protein-lysine demethylase acting beyond chromatin, demethylating p38α at K165 to suppress its phosphorylation and pro-tumor activity.","evidence":"Co-IP, in vitro demethylation assay with K165 site-directed mutagenesis, phosphorylation readouts, and lung cancer xenografts","pmids":["39636854"],"confidence":"High","gaps":["Breadth of non-histone substrate repertoire unknown","Relative contribution of histone vs protein substrate demethylation to phenotypes not quantified"]},{"year":2024,"claim":"Tested pharmacological enhancement of KDM5D, with curcumin increasing its expression and activity to suppress AR/EMT signaling in castration-resistant prostate cancer.","evidence":"Curcumin-induced KDM5D activation, demethylase activity assay, invasion assay, and AR/EMT marker analysis","pmids":["39218854"],"confidence":"Low","gaps":["Effect inferred from correlative activity/expression changes without catalytic-site mutagenesis","Off-target effects of curcumin not excluded"]},{"year":null,"claim":"The full substrate spectrum of KDM5D as a dual histone- and protein-lysine demethylase, and what determines its opposing tumor-suppressive versus pro-tolerance roles across tissues, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of KDM5D substrate recognition","Context determinants of tumor-suppressor vs oncogenic behavior undefined","Genome-wide direct-target catalogue incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[11]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[2,3,4]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[2,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,8,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,5,8,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,8,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,10,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,10]}],"complexes":[],"partners":["MSH5","AR","MAPK14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BY66","full_name":"Lysine-specific demethylase 5D","aliases":["Histocompatibility Y antigen","H-Y","Histone demethylase JARID1D","Jumonji/ARID domain-containing protein 1D","Protein SmcY","[histone H3]-trimethyl-L-lysine(4) demethylase 5D"],"length_aa":1539,"mass_kda":174.1,"function":"Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. May play a role in spermatogenesis. Involved in transcriptional repression of diverse metastasis-associated genes; in this function seems to cooperate with ZMYND8. Suppresses prostate cancer cell invasion. Regulates androgen receptor (AR) transcriptional activity by demethylating H3K4me3 active transcription marks","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BY66/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM5D","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":383,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KDM5D","total_profiled":1310},"omim":[{"mim_id":"617410","title":"ZINC FINGER PROTEIN 419; ZNF419","url":"https://www.omim.org/entry/617410"},{"mim_id":"426000","title":"LYSINE DEMETHYLASE 5D; KDM5D","url":"https://www.omim.org/entry/426000"},{"mim_id":"400022","title":"PROTOCADHERIN 11, Y-LINKED; PCDH11Y","url":"https://www.omim.org/entry/400022"},{"mim_id":"400017","title":"THYMOSIN, BETA-4, Y CHROMOSOME; TMSB4Y","url":"https://www.omim.org/entry/400017"},{"mim_id":"400005","title":"UBIQUITIN-SPECIFIC PROTEASE 9, Y CHROMOSOME; USP9Y","url":"https://www.omim.org/entry/400005"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KDM5D"},"hgnc":{"alias_symbol":["KIAA0234"],"prev_symbol":["HYA","HY","SMCY","JARID1D"]},"alphafold":{"accession":"Q9BY66","domains":[{"cath_id":"2.60.120.650","chopping":"17-78_374-608","consensus_level":"high","plddt":88.0148,"start":17,"end":608},{"cath_id":"1.10.150.60","chopping":"102-190","consensus_level":"medium","plddt":73.9642,"start":102,"end":190},{"cath_id":"-","chopping":"611-772","consensus_level":"medium","plddt":91.3765,"start":611,"end":772},{"cath_id":"-","chopping":"1005-1066","consensus_level":"medium","plddt":88.286,"start":1005,"end":1066}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY66","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY66-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY66-F1-predicted_aligned_error_v6.png","plddt_mean":72.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM5D","jax_strain_url":"https://www.jax.org/strain/search?query=KDM5D"},"sequence":{"accession":"Q9BY66","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BY66.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BY66/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY66"}},"corpus_meta":[{"pmid":"7667640","id":"PMC_7667640","title":"Human H-Y: a male-specific histocompatibility antigen derived from the SMCY protein.","date":"1995","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7667640","citation_count":311,"is_preprint":false},{"pmid":"70400","id":"PMC_70400","title":"Responsiveness to HY antigen Ir gene complementation and target cell specificity.","date":"1977","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/70400","citation_count":245,"is_preprint":false},{"pmid":"6403941","id":"PMC_6403941","title":"Identification of the hypusine-containing protein hy+ as translation initiation factor eIF-4D.","date":"1983","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/6403941","citation_count":209,"is_preprint":false},{"pmid":"7544442","id":"PMC_7544442","title":"Identification of a mouse male-specific transplantation antigen, H-Y.","date":"1995","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/7544442","citation_count":163,"is_preprint":false},{"pmid":"10679124","id":"PMC_10679124","title":"The human UTY gene encodes a novel HLA-B8-restricted H-Y antigen.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10679124","citation_count":149,"is_preprint":false},{"pmid":"27185910","id":"PMC_27185910","title":"Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27185910","citation_count":132,"is_preprint":false},{"pmid":"1856178","id":"PMC_1856178","title":"Mutational analysis and characterization of the Escherichia coli hya operon, which encodes [NiFe] hydrogenase 1.","date":"1991","source":"Journal of 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Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30578984","citation_count":10,"is_preprint":false},{"pmid":"37866328","id":"PMC_37866328","title":"Baicalin mitigates nephropathogenic infectious bronchitis virus infection-induced spleen injury via modulation of mitophagy and macrophage polarization in Hy-Line chick.","date":"2023","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37866328","citation_count":10,"is_preprint":false},{"pmid":"39636854","id":"PMC_39636854","title":"KDM5D histone demethylase mediates p38α inactivation via its enzymatic activity to inhibit cancer progression.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39636854","citation_count":9,"is_preprint":false},{"pmid":"36982384","id":"PMC_36982384","title":"KDM5D Histone Demethylase Identifies Platinum-Tolerant Head and Neck Cancer Cells Vulnerable to Mitotic Catastrophe.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36982384","citation_count":9,"is_preprint":false},{"pmid":"34273914","id":"PMC_34273914","title":"Increased Mars2 expression upon microRNA-4661-5p-mediated KDM5D downregulation is correlated with malignant degree of gastric cancer cells.","date":"2021","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/34273914","citation_count":9,"is_preprint":false},{"pmid":"3503714","id":"PMC_3503714","title":"Mapping the H-Y gene.","date":"1987","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/3503714","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50561,"output_tokens":3660,"usd":0.103291,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11351,"output_tokens":3985,"usd":0.07819,"stage2_stop_reason":"end_turn"},"total_usd":0.181481,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"KDM5D (SMCY) encodes an 11-residue peptide epitope that is presented by HLA-B7 as a human H-Y minor histocompatibility antigen; the homologous X-chromosome protein SMCX differs by two amino acid residues in the same region, explaining male specificity.\",\n      \"method\": \"Peptide elution from HLA molecules, mass spectrometry, T-cell cytotoxicity assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical identification of the peptide by mass spectrometry combined with functional T-cell assay, replicated in two independent papers (PMID:7667640 and PMID:7544442)\",\n      \"pmids\": [\"7667640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The mouse Smcy gene encodes the H-Y Kk epitope defined by the octamer peptide TENSGKDI; no equivalent peptide is found in the X-homologue Smcx, establishing Smcy (KDM5D ortholog) as a source of male-specific transplantation antigen peptides.\",\n      \"method\": \"Peptide identification, T-cell cytotoxicity assay, gene mapping\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — peptide identified biochemically, functional T-cell recognition confirmed, independent replication across mouse and human systems\",\n      \"pmids\": [\"7544442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SMCY (KDM5D) forms a distinct protein complex with MSH5 (a meiosis-regulatory protein) in human testicular germ cells (NEC8 line), co-localizes with MSH5 at a specific stage of meiotic prophase during murine spermatogenesis, and displays histone H3K4 demethylase activity in biochemical assays.\",\n      \"method\": \"Co-immunoprecipitation/biochemical protein identification, histone demethylase activity assay, immunohistochemistry, co-localization\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with demethylase activity assay and co-localization, single lab with two orthogonal methods\",\n      \"pmids\": [\"18459961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM5D physically interacts with the androgen receptor (AR) in the nucleus and regulates AR transcriptional activity by demethylating H3K4me3 marks; knockdown of KDM5D dysregulates AR signaling and confers docetaxel resistance in prostate cancer cells in the presence of dihydrotestosterone.\",\n      \"method\": \"Co-immunoprecipitation (nuclear fraction), RNA-seq, ChIP, siRNA knockdown, cell viability assay\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating physical interaction, ChIP showing H3K4me3 changes at AR target genes, functional rescue experiments, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27185910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM5D preferentially binds to promoter regions enriched for cell-cycle transcription factor motifs (by ChIP-seq); loss of KDM5D leads to dysregulated H3K4me3 marks, accelerated cell cycle progression and mitotic entry, increased DNA-replication stress, and activation of ATR kinase; ATR inhibition in KDM5D-deficient prostate cancer cells enhances DNA damage and induces apoptosis.\",\n      \"method\": \"ChIP-seq, FISH (Y chromosome deletion), siRNA/shRNA knockdown, ATR inhibitor treatment, apoptosis assay\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq with functional loss-of-function, mechanistic epistasis with ATR pathway, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"29863497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM5D demethylates H3K4me3 at the promoter of CUL4A, reducing CUL4A expression, which leads to decreased ZEB1 and altered p21/p53 levels; knockdown of KDM5D in gastric cancer cells increases cell migration, invasion, and tumor formation in vivo, while overexpression suppresses epithelial-mesenchymal transition.\",\n      \"method\": \"ChIP-qPCR (H3K4me3 at CUL4A promoter), siRNA knockdown, transwell migration/invasion assay, in vivo xenograft\",\n      \"journal\": \"Journal of Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing demethylation at specific promoter with functional downstream consequences, single lab with multiple methods\",\n      \"pmids\": [\"30864186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM5D knockdown via siRNA in cardiomyocyte differentiation models causes accumulation of cells in S-phase, impaired progression to cardiomyocytes, absence of spontaneous beating, and altered cardiac progenitor marker expression; KDM5D is upregulated during cardiac mesoderm stage of development and acts cooperatively with its X-homologue KDM5C.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis (S-phase accumulation), expression profiling of cardiac progenitor markers, beating cell assay\",\n      \"journal\": \"Journal of Proteome Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular phenotype readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31560558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Combined genetic deletion of Kdm5c and Kdm5d (but not either alone) in mice results in noncompaction cardiomyopathy with prominent trabecular extension and thin compacted myocardium, demonstrating that Kdm5d and Kdm5c have conserved and partially redundant roles in heart development.\",\n      \"method\": \"Genetic mouse knockouts (compound hemizygous and homozygous), histological examination of cardiac phenotype\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined cardiac phenotype, epistasis between X and Y paralogs established, single lab\",\n      \"pmids\": [\"32081420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM5D suppresses E2F1 expression by mediating H3K4me3 demethylation at the E2F1 locus; reduced E2F1 in turn decreases transcription of FKBP4 (confirmed by ChIP-qPCR and luciferase reporter assays); overexpression of FKBP4 rescues the anti-tumor effect of KDM5D in colorectal cancer cells.\",\n      \"method\": \"ChIP-qPCR (H3K4me3 at E2F1 promoter), luciferase reporter assay, overexpression/rescue experiments, in vitro and in vivo growth/metastasis assays\",\n      \"journal\": \"Biochemical Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR plus reporter assay plus rescue experiment defining a KDM5D→E2F1→FKBP4 pathway, single lab\",\n      \"pmids\": [\"34688635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-4661-5p targets KDM5D mRNA and downregulates KDM5D expression, leading to increased H3K4me3 at the Mars2 promoter and elevated Mars2 transcription, which promotes gastric cancer cell proliferation, migration, and invasion; direct KDM5D occupancy at the Mars2 promoter was demonstrated by ChIP.\",\n      \"method\": \"miRNA overexpression/inhibition, ChIP (H3K4me3 at Mars2 promoter), siRNA KDM5D knockdown, cell functional assays\",\n      \"journal\": \"Cell Biology International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at specific target locus with functional rescue, single lab\",\n      \"pmids\": [\"34273914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In colorectal cancer, KRAS*-mediated activation of the STAT4 transcription factor drives transcriptional upregulation of KDM5D; KDM5D-dependent H3K4 demethylation represses regulators of epithelial tight junctions and MHC class I components; Kdm5d deletion increases tight junction integrity, decreases cell invasiveness, and enhances CD8+ T-cell-mediated cancer cell killing, while Kdm5d transgenic expression increases tumor invasiveness in vivo.\",\n      \"method\": \"Transgenic/conditional knockout mouse models, transcriptomic and chromatin mark analysis (ChIP-seq inferred), CD8+ T-cell killing assay, in vivo tumor invasion assay, STAT4 pathway analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple complementary genetic gain- and loss-of-function models in vivo, integrated molecular and functional readouts, cross-species validation, published in high-tier journal with rigorous controls\",\n      \"pmids\": [\"37344599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5D directly interacts with p38α (MAPK14) and demethylates p38α at lysine 165 (K165); K165 methylation promotes p38α phosphorylation and activation, while KDM5D-mediated demethylation inhibits p38α phosphorylation, thereby suppressing tumor cell proliferation and migration in non-small cell lung cancer xenograft models.\",\n      \"method\": \"Co-immunoprecipitation (KDM5D–p38α interaction), in vitro demethylation assay, site-directed mutagenesis (K165), phosphorylation assays, KDM5D knockdown/overexpression, xenograft tumor model\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro demethylation assay with mutagenesis (K165) plus Co-IP, phosphorylation mechanistic readout, in vivo tumor model; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"39636854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Curcumin enhances both the expression and demethylase activity of KDM5D (JARID1D), and increased KDM5D activity suppresses AR and EMT signaling cascades to inhibit invasion of castration-resistant prostate cancer cells.\",\n      \"method\": \"KDM5D overexpression/pharmacological activation by curcumin, demethylase activity assay, invasion assay, AR and EMT marker analysis\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological activation without direct mutagenesis of KDM5D catalytic site; mechanism inferred from correlative activity and expression changes\",\n      \"pmids\": [\"39218854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM5D upregulation promotes platinum (cisplatin) tolerance in head and neck squamous cell carcinoma by modulating Aurora Kinase B (AURKB) mRNA levels; KDM5D knockdown reduces persister-cell tolerance to platinum agents, causes DNA damage checkpoint deregulation and abnormal mitosis; AURKB inhibition overcomes the tolerance, identifying a KDM5D/AURKB regulatory axis.\",\n      \"method\": \"KDM5D knockdown (siRNA/shRNA), RT-qPCR (AURKB mRNA), cell cycle analysis, in vitro and in vivo (xenograft) drug tolerance assays\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular (AURKB mRNA) and cellular (mitotic catastrophe) phenotype, in vivo validation, single lab\",\n      \"pmids\": [\"36982384\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM5D (SMCY/JARID1D) is a Y-chromosome-encoded histone H3K4 demethylase that removes methyl marks from H3K4me3 at gene promoters to regulate transcription; it physically interacts with the androgen receptor (in the nucleus) and with p38α (in the cytoplasm), demethylating p38α at K165 to suppress its phosphorylation and activity; it also forms a spermatogenesis-specific complex with the meiotic regulator MSH5; downstream, KDM5D suppresses E2F1, CUL4A, FKBP4, Mars2, and MHC-I/tight-junction gene programs, and its loss accelerates cell-cycle progression, increases DNA-replication stress with ATR activation, promotes epithelial-mesenchymal transition, and drives tumor invasiveness, while its gain-of-function suppresses these oncogenic phenotypes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM5D (SMCY/JARID1D) is a Y-chromosome-encoded histone H3K4 demethylase that shapes transcriptional programs governing cell-cycle progression, genome stability, and tumor invasiveness [#4, #10]. Through removal of activating H3K4me3 marks at target promoters, it represses gene programs including E2F1 (and its downstream effector FKBP4), CUL4A, Mars2, and regulators of epithelial tight junctions and MHC class I [#5, #8, #9, #10]; loss of KDM5D accelerates cell-cycle progression and mitotic entry, increases DNA-replication stress with ATR activation, and promotes epithelial-mesenchymal transition and invasiveness, whereas its activity suppresses these phenotypes [#4, #5, #10]. KDM5D was originally identified as the source of male-specific H-Y minor histocompatibility antigen peptides presented by MHC, distinguishing it from its X-homologue [#0, #1]. Beyond chromatin, KDM5D acts as a protein-lysine demethylase: it binds p38\\u03b1 (MAPK14) and demethylates it at K165 to suppress p38\\u03b1 phosphorylation and activity [#11], and it physically associates with the androgen receptor in the nucleus to modulate AR transcriptional output, with its loss conferring docetaxel resistance in prostate cancer [#3]. In germ cells, KDM5D forms a complex with the meiotic regulator MSH5 during spermatogenesis [#2]. It cooperates with its X-paralog KDM5C in heart development [#6, #7]. Pharmacologically, its activity is regulated upstream by miR-4661-5p and by KRAS*/STAT4 signaling [#9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established KDM5D/SMCY as the molecular source of the male-specific H-Y minor histocompatibility antigen, explaining sex-mismatched transplant rejection at the level of a defined peptide epitope.\",\n      \"evidence\": \"Peptide elution from HLA molecules with mass spectrometry and T-cell cytotoxicity assays, in human (HLA-B7) and mouse (Kk) systems\",\n      \"pmids\": [\"7667640\", \"7544442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address the enzymatic or chromatin function of the protein\", \"Antigen presentation does not establish a cellular role for KDM5D\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that the SMCY protein possesses intrinsic histone H3K4 demethylase activity and physically partners with the meiotic regulator MSH5 in germ cells, assigning it a chromatin-modifying enzyme function and a spermatogenesis-specific complex.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro histone demethylase assay, and immunohistochemical co-localization during murine meiotic prophase\",\n      \"pmids\": [\"18459961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the MSH5 complex in meiosis not defined\", \"Genome-wide demethylase targets not mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected KDM5D demethylase activity to androgen receptor signaling, linking its loss to therapy resistance in prostate cancer.\",\n      \"evidence\": \"Nuclear-fraction Co-IP, ChIP for H3K4me3 at AR targets, RNA-seq, siRNA knockdown, and docetaxel viability assays in prostate cancer cells\",\n      \"pmids\": [\"27185910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AR-binding interface not mapped\", \"Whether AR regulation requires catalytic activity not isolated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined KDM5D as a genome-wide guardian of cell-cycle and replication control, showing its loss creates ATR-dependent replication stress that can be exploited therapeutically.\",\n      \"evidence\": \"ChIP-seq mapping to cell-cycle TF-motif promoters, loss-of-function knockdown, ATR inhibitor treatment, and apoptosis assays in prostate cancer cells\",\n      \"pmids\": [\"29863497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific direct target genes mediating the replication-stress phenotype not individually validated\", \"Catalytic dependence of phenotype not formally separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended KDM5D function to suppression of EMT and invasion via promoter-specific H3K4me3 demethylation of CUL4A in gastric cancer.\",\n      \"evidence\": \"ChIP-qPCR at CUL4A promoter, siRNA knockdown, transwell migration/invasion assays, and xenografts\",\n      \"pmids\": [\"30864186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream ZEB1/p21/p53 effects correlative\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated KDM5D, cooperatively with its X-paralog KDM5C, in cardiac differentiation and cell-cycle control during development.\",\n      \"evidence\": \"siRNA knockdown in cardiomyocyte differentiation models with cell-cycle analysis and cardiac marker profiling (2019); compound Kdm5c/Kdm5d mouse knockouts with cardiac histology (2020)\",\n      \"pmids\": [\"31560558\", \"32081420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets in cardiac tissue not identified\", \"Degree of paralog redundancy versus distinct function not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped specific KDM5D-controlled oncogenic transcriptional axes, defining a KDM5D\\u2192E2F1\\u2192FKBP4 cascade and direct repression of Mars2, the latter relieved by miR-4661-5p.\",\n      \"evidence\": \"ChIP-qPCR at E2F1 and Mars2 promoters, luciferase reporters, miRNA over/under-expression, and rescue experiments in colorectal and gastric cancer cells\",\n      \"pmids\": [\"34688635\", \"34273914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Individual axes characterized in single cancer models\", \"Whether axes operate concurrently in the same cells not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed KDM5D downstream of KRAS*/STAT4 signaling as an immune-evasion and invasion driver that represses tight-junction and MHC-I genes, with gain- and loss-of-function reversing CD8+ T-cell killing and invasiveness.\",\n      \"evidence\": \"Transgenic and conditional Kdm5d mouse models, transcriptomic/chromatin analysis, CD8+ T-cell killing assays, and in vivo invasion assays in colorectal cancer\",\n      \"pmids\": [\"37344599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin occupancy at each repressed locus not individually resolved\", \"Generalizability beyond KRAS-mutant context unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a context-dependent role in which KDM5D upregulation promotes platinum tolerance through AURKB regulation in head and neck cancer, contrasting with its tumor-suppressive roles elsewhere.\",\n      \"evidence\": \"Knockdown, RT-qPCR for AURKB, cell-cycle analysis, AURKB inhibition, and in vivo drug-tolerance assays\",\n      \"pmids\": [\"36982384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of AURKB mRNA regulation (direct vs indirect) not resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that KDM5D is a protein-lysine demethylase acting beyond chromatin, demethylating p38\\u03b1 at K165 to suppress its phosphorylation and pro-tumor activity.\",\n      \"evidence\": \"Co-IP, in vitro demethylation assay with K165 site-directed mutagenesis, phosphorylation readouts, and lung cancer xenografts\",\n      \"pmids\": [\"39636854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Breadth of non-histone substrate repertoire unknown\", \"Relative contribution of histone vs protein substrate demethylation to phenotypes not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Tested pharmacological enhancement of KDM5D, with curcumin increasing its expression and activity to suppress AR/EMT signaling in castration-resistant prostate cancer.\",\n      \"evidence\": \"Curcumin-induced KDM5D activation, demethylase activity assay, invasion assay, and AR/EMT marker analysis\",\n      \"pmids\": [\"39218854\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Effect inferred from correlative activity/expression changes without catalytic-site mutagenesis\", \"Off-target effects of curcumin not excluded\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full substrate spectrum of KDM5D as a dual histone- and protein-lysine demethylase, and what determines its opposing tumor-suppressive versus pro-tolerance roles across tissues, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of KDM5D substrate recognition\", \"Context determinants of tumor-suppressor vs oncogenic behavior undefined\", \"Genome-wide direct-target catalogue incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 8, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 5, 8, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 8, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 10, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MSH5\", \"AR\", \"MAPK14\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}