{"gene":"ANKDD1A","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2018,"finding":"ANKDD1A directly interacts with FIH1 (factor inhibiting HIF-1) and inhibits the transcriptional activity of HIF1α by upregulating FIH1; ANKDD1A also decreases the half-life of HIF1α through FIH1 upregulation, leading to decreased glucose uptake, reduced lactate production, inhibition of autophagy, and induction of apoptosis in glioblastoma cells under hypoxia.","method":"Co-immunoprecipitation (direct interaction with FIH1), functional assays measuring HIF1α stability/half-life, glucose uptake and lactate production assays, autophagy and apoptosis assays in GBM cells with ANKDD1A expression manipulation under hypoxic conditions","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction identified, multiple orthogonal functional readouts (HIF1α stability, metabolic outputs, autophagy, apoptosis), single lab","pmids":["30082910"],"is_preprint":false},{"year":2011,"finding":"ANKDD1A promoter is hypermethylated in primary glioma relative to normal brain tissue, and its reduced expression is associated with aberrant promoter methylation and altered histone modifications; induction of miR-185 overexpression (which targets DNMT1) restored ANKDD1A expression in glioma cells.","method":"MeDIP-chip genome-wide methylation profiling, Sequenom MassARRAY methylation validation, chromatin immunoprecipitation, quantitative RT-PCR, miR-185 overexpression in glioma cell lines","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal epigenetic methods (MeDIP, ChIP, MassARRAY) in 40 samples plus cell lines, single lab","pmids":["21962230"],"is_preprint":false}],"current_model":"ANKDD1A is a tumor suppressor whose promoter is silenced by hypermethylation in glioma; when expressed, it directly binds FIH1 to upregulate its activity, thereby destabilizing HIF1α and suppressing HIF1α-driven transcription, which reduces glucose uptake, lactate production, and autophagy while promoting apoptosis in the hypoxic glioblastoma microenvironment."},"narrative":{"mechanistic_narrative":"ANKDD1A functions as a negative regulator of the hypoxic transcriptional response in glioma, acting as a tumor suppressor whose loss favors hypoxic adaptation of tumor cells [PMID:30082910, PMID:21962230]. Mechanistically, ANKDD1A directly binds FIH1 (factor inhibiting HIF-1) and upregulates its activity, which destabilizes HIF1α by shortening its half-life and represses HIF1α-driven transcription; the downstream consequences include reduced glucose uptake and lactate production, inhibition of autophagy, and induction of apoptosis in glioblastoma cells under hypoxia [PMID:30082910]. ANKDD1A expression is suppressed in primary glioma through promoter hypermethylation and altered histone modifications, and can be restored via miR-185-mediated targeting of DNMT1 [PMID:21962230]. Beyond its FIH1/HIF1α axis in glioma, no further molecular detail has been characterized in the available corpus.","teleology":[{"year":2011,"claim":"Established that ANKDD1A is epigenetically silenced in glioma, framing it as a candidate tumor suppressor whose loss is driven by aberrant promoter methylation rather than mutation.","evidence":"Genome-wide MeDIP-chip, MassARRAY methylation validation, ChIP, and miR-185 overexpression in primary glioma samples and cell lines","pmids":["21962230"],"confidence":"Medium","gaps":["Does not establish the molecular function of the ANKDD1A protein itself","Causal contribution of silencing to tumorigenesis not directly demonstrated","miR-185/DNMT1 link to ANKDD1A is correlative restoration, not a defined regulatory circuit"]},{"year":2018,"claim":"Defined the molecular mechanism by which ANKDD1A acts, showing it binds FIH1 to suppress HIF1α signaling and reprogram hypoxic metabolism, autophagy, and survival in glioblastoma.","evidence":"Co-immunoprecipitation for FIH1 interaction plus HIF1α half-life, glucose uptake, lactate, autophagy, and apoptosis assays in GBM cells under hypoxia","pmids":["30082910"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","Structural basis of the ANKDD1A–FIH1 interaction and how it upregulates FIH1 activity not resolved","Whether ANKDD1A acts in tissues outside glioma is untested"]},{"year":null,"claim":"Whether ANKDD1A has functions beyond the FIH1/HIF1α axis and a role in normal physiology remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or domain-level mechanism for FIH1 activation","No in vivo tumor suppression demonstration in the corpus","No partners or substrates beyond FIH1 identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0]}],"complexes":[],"partners":["FIH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q495B1","full_name":"Ankyrin repeat and death domain-containing protein 1A","aliases":[],"length_aa":522,"mass_kda":57.5,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q495B1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANKDD1A","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ANKDD1A","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANKDD1A"},"hgnc":{"alias_symbol":["FLJ25870"],"prev_symbol":[]},"alphafold":{"accession":"Q495B1","domains":[{"cath_id":"1.25.40.20","chopping":"2-123","consensus_level":"medium","plddt":86.7525,"start":2,"end":123},{"cath_id":"1.25.40.20","chopping":"285-376","consensus_level":"medium","plddt":96.6034,"start":285,"end":376},{"cath_id":"1.10.533,1.10.533","chopping":"407-508","consensus_level":"high","plddt":85.7335,"start":407,"end":508}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q495B1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q495B1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q495B1-F1-predicted_aligned_error_v6.png","plddt_mean":89.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANKDD1A","jax_strain_url":"https://www.jax.org/strain/search?query=ANKDD1A"},"sequence":{"accession":"Q495B1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q495B1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q495B1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q495B1"}},"corpus_meta":[{"pmid":"21962230","id":"PMC_21962230","title":"MiR-185 targets the DNA methyltransferases 1 and regulates global DNA methylation in human glioma.","date":"2011","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21962230","citation_count":105,"is_preprint":false},{"pmid":"30082910","id":"PMC_30082910","title":"Hypermethylated gene ANKDD1A is a candidate tumor suppressor that interacts with FIH1 and decreases HIF1α stability to inhibit cell autophagy in the glioblastoma multiforme hypoxia microenvironment.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30082910","citation_count":40,"is_preprint":false},{"pmid":"30651372","id":"PMC_30651372","title":"The Germline Variants rs61757955 and rs34988193 Are Predictive of Survival in Lower Grade Glioma Patients.","date":"2019","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/30651372","citation_count":7,"is_preprint":false},{"pmid":"35116461","id":"PMC_35116461","title":"ANKDD1A may serve as a critical gene in the immune microenvironment of breast cancer.","date":"2021","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35116461","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4258,"output_tokens":672,"usd":0.011427,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7070,"output_tokens":1306,"usd":0.034,"stage2_stop_reason":"end_turn"},"total_usd":0.045427,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"ANKDD1A directly interacts with FIH1 (factor inhibiting HIF-1) and inhibits the transcriptional activity of HIF1α by upregulating FIH1; ANKDD1A also decreases the half-life of HIF1α through FIH1 upregulation, leading to decreased glucose uptake, reduced lactate production, inhibition of autophagy, and induction of apoptosis in glioblastoma cells under hypoxia.\",\n      \"method\": \"Co-immunoprecipitation (direct interaction with FIH1), functional assays measuring HIF1α stability/half-life, glucose uptake and lactate production assays, autophagy and apoptosis assays in GBM cells with ANKDD1A expression manipulation under hypoxic conditions\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction identified, multiple orthogonal functional readouts (HIF1α stability, metabolic outputs, autophagy, apoptosis), single lab\",\n      \"pmids\": [\"30082910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ANKDD1A promoter is hypermethylated in primary glioma relative to normal brain tissue, and its reduced expression is associated with aberrant promoter methylation and altered histone modifications; induction of miR-185 overexpression (which targets DNMT1) restored ANKDD1A expression in glioma cells.\",\n      \"method\": \"MeDIP-chip genome-wide methylation profiling, Sequenom MassARRAY methylation validation, chromatin immunoprecipitation, quantitative RT-PCR, miR-185 overexpression in glioma cell lines\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal epigenetic methods (MeDIP, ChIP, MassARRAY) in 40 samples plus cell lines, single lab\",\n      \"pmids\": [\"21962230\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANKDD1A is a tumor suppressor whose promoter is silenced by hypermethylation in glioma; when expressed, it directly binds FIH1 to upregulate its activity, thereby destabilizing HIF1α and suppressing HIF1α-driven transcription, which reduces glucose uptake, lactate production, and autophagy while promoting apoptosis in the hypoxic glioblastoma microenvironment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANKDD1A functions as a negative regulator of the hypoxic transcriptional response in glioma, acting as a tumor suppressor whose loss favors hypoxic adaptation of tumor cells [#0, #1]. Mechanistically, ANKDD1A directly binds FIH1 (factor inhibiting HIF-1) and upregulates its activity, which destabilizes HIF1\\u03b1 by shortening its half-life and represses HIF1\\u03b1-driven transcription; the downstream consequences include reduced glucose uptake and lactate production, inhibition of autophagy, and induction of apoptosis in glioblastoma cells under hypoxia [#0]. ANKDD1A expression is suppressed in primary glioma through promoter hypermethylation and altered histone modifications, and can be restored via miR-185-mediated targeting of DNMT1 [#1]. Beyond its FIH1/HIF1\\u03b1 axis in glioma, no further molecular detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that ANKDD1A is epigenetically silenced in glioma, framing it as a candidate tumor suppressor whose loss is driven by aberrant promoter methylation rather than mutation.\",\n      \"evidence\": \"Genome-wide MeDIP-chip, MassARRAY methylation validation, ChIP, and miR-185 overexpression in primary glioma samples and cell lines\",\n      \"pmids\": [\"21962230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not establish the molecular function of the ANKDD1A protein itself\",\n        \"Causal contribution of silencing to tumorigenesis not directly demonstrated\",\n        \"miR-185/DNMT1 link to ANKDD1A is correlative restoration, not a defined regulatory circuit\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the molecular mechanism by which ANKDD1A acts, showing it binds FIH1 to suppress HIF1\\u03b1 signaling and reprogram hypoxic metabolism, autophagy, and survival in glioblastoma.\",\n      \"evidence\": \"Co-immunoprecipitation for FIH1 interaction plus HIF1\\u03b1 half-life, glucose uptake, lactate, autophagy, and apoptosis assays in GBM cells under hypoxia\",\n      \"pmids\": [\"30082910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding without independent replication\",\n        \"Structural basis of the ANKDD1A\\u2013FIH1 interaction and how it upregulates FIH1 activity not resolved\",\n        \"Whether ANKDD1A acts in tissues outside glioma is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether ANKDD1A has functions beyond the FIH1/HIF1\\u03b1 axis and a role in normal physiology remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural or domain-level mechanism for FIH1 activation\",\n        \"No in vivo tumor suppression demonstration in the corpus\",\n        \"No partners or substrates beyond FIH1 identified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FIH1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":2,"faith_total":3,"faith_pct":66.66666666666667}}