{"gene":"ZNF703","run_date":"2026-06-11T09:02:07","timeline":{"discoveries":[{"year":2011,"finding":"ZNF703 (Zeppo1) complexes with Groucho co-repressor and represses E-cadherin transcription, as well as Wnt and TGFβ reporter expression, in mammary epithelial cells.","method":"Transcriptional reporter assays, co-immunoprecipitation, knockdown/overexpression in cell lines and mouse breast cancer model","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional data (reporter assays + co-IP with Groucho), supported by in vivo mouse metastasis model with defined molecular readouts","pmids":["21317240"],"is_preprint":false},{"year":2011,"finding":"ZNF703 is a co-factor of a nuclear complex comprising DCAF7, PHB2, and NCOR2, identified by mass spectrometry in luminal breast cancer cells.","method":"Mass spectrometry/co-immunoprecipitation of ZNF703-containing nuclear complex","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mass spectrometry identification in single study, limited functional follow-up on individual complex members","pmids":["21328542"],"is_preprint":false},{"year":2011,"finding":"ZNF703 overexpression activates stem cell-related gene expression and is implicated in regulation of ER and E2F1 transcription factors in luminal breast cancer cells.","method":"Overexpression in MCF7 cells with gene expression profiling","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, gene expression changes after overexpression without direct binding or mechanistic validation","pmids":["21328542"],"is_preprint":false},{"year":2011,"finding":"ZNF703 overexpression in MCF7 cells modifies TGFβ effects on proliferation, and overexpression in normal human breast epithelial cells enhances luminal progenitor colony-forming frequency.","method":"Overexpression and knockdown in cell lines, in vitro colony-forming assays","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in single lab, two orthogonal readouts (proliferation and colony forming)","pmids":["21337521"],"is_preprint":false},{"year":2011,"finding":"ZNF703 (Zeppo1) promotes expression of metastasis-associated p120-catenin isoform 1 and alters p120-catenin localization upon cell contact with extracellular matrix.","method":"Overexpression/knockdown in mammary epithelial cells with immunofluorescence and Western blotting","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, two orthogonal methods in single lab","pmids":["21317240"],"is_preprint":false},{"year":2008,"finding":"Nlz1/Znf703 acts as a transcriptional repressor requiring histone deacetylase (HDAC) activity; repression was demonstrated in cell-based reporter assays and in developing zebrafish embryos, and Nlz1 promotes histone deacetylation at target promoters.","method":"Luciferase reporter assays (4 cell lines), pharmacological HDAC inhibition, transgenic zebrafish reporter line with ChIP for histone acetylation, structure-function (domain deletion) analysis","journal":"BMC developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (reporter assay, pharmacological inhibition, ChIP in vivo, structure-function), replicated across multiple cell lines and in zebrafish","pmids":["19014486"],"is_preprint":false},{"year":2013,"finding":"ZNF703 overexpression in MCF-7 cells activates the Akt/mTOR signaling pathway and downregulates ERα, contributing to tamoxifen resistance; mTOR inhibition combined with tamoxifen overcomes this resistance in ZNF703-overexpressing cells.","method":"Overexpression and siRNA knockdown in breast cancer cell lines, Western blotting for pathway components, cell viability assays with drug treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway activation confirmed by Western blot and rescue with mTOR inhibitor, single lab with multiple orthogonal readouts","pmids":["23991038"],"is_preprint":false},{"year":2013,"finding":"Human NLZ1/ZNF703 contains six evolutionarily conserved domains, three specific to NET proteins; specific domains are necessary for proper subcellular distribution and transcriptional repression, but the Groucho-interaction domain is not required for interaction with Groucho co-repressors.","method":"Domain deletion mutant analysis, subcellular localization imaging, transcriptional reporter assays, co-immunoprecipitation","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function analysis with multiple domain mutants and functional readouts in single lab","pmids":["22886885"],"is_preprint":false},{"year":2015,"finding":"nlz1/Znf703 is required for ciliogenesis in zebrafish: morpholino knockdown reduces cilia number in Kupffer's vesicle, pronephros, and neural floorplate; Nlz1 acts downstream of Foxj1a and Wnt8a/canonical Wnt signaling and positively regulates Wnt11/non-canonical Wnt signaling to promote motile cilia formation.","method":"Morpholino-mediated knockdown in zebrafish, epistasis analysis with Foxj1a and Wnt pathway components, in vitro and in vivo assays","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in zebrafish with defined pathway placement, single lab","pmids":["26327644"],"is_preprint":false},{"year":2017,"finding":"Znf703/Nlz1 acts downstream of Pax3 and Zic1 in Xenopus to repress posterior hindbrain gene expression and regulate neural crest formation; its transcriptional repressor activity is critical for hindbrain patterning.","method":"Morpholino knockdown and overexpression in Xenopus, microarray-based identification as Pax3/Zic1 target, in situ hybridization for segmental gene markers","journal":"Genesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in Xenopus, two perturbation directions (knockdown and overexpression), single lab","pmids":["29086464"],"is_preprint":false},{"year":2019,"finding":"Znf703 is an RAR- and Wnt-inducible transcription factor; its Buttonhead domain (not the Groucho-repression domain) is required for transcriptional repression affecting mesoderm, neural crest, and placode development in Xenopus.","method":"Overexpression and knockdown in Xenopus, domain mutant analysis (Groucho-repression domain mutation vs. Buttonhead domain mutation), in situ hybridization","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function with domain mutations in vivo, single lab","pmids":["31164691"],"is_preprint":false},{"year":2020,"finding":"ZNF703 interacts with HE4 protein, and HE4 promotes nuclear translocation of ZNF703; ZNF703 directly binds the enhancer region of PEA15 to promote PEA15 transcription in ovarian cancer cells.","method":"Immunofluorescence co-localization, co-immunoprecipitation, ChIP-sequencing, dual luciferase reporter assay, ChIP-PCR, in vivo xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including ChIP-seq, co-IP, reporter assay, and in vivo validation in single rigorous study","pmids":["33246486"],"is_preprint":false},{"year":2020,"finding":"ZNF703 acts as a transcription factor that binds to the LINC00460 promoter region to activate its transcription in ovarian cancer cells.","method":"Chromatin immunoprecipitation (ChIP) assay, JASPAR database prediction, rescue experiments","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP assay confirms binding, single lab, single method for the binding claim","pmids":["32382355"],"is_preprint":false},{"year":2020,"finding":"ZNF703 transcriptionally activates linc-UBC1 by binding to its promoter region in glioma cells, promoting proliferation and invasion.","method":"RNA binding protein immunoprecipitation (RIP), dual-luciferase reporter assay, rescue experiments","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP and luciferase assay in single lab, limited mechanistic resolution","pmids":["32271436"],"is_preprint":false},{"year":2024,"finding":"The E3 ubiquitin ligase PARK2 interacts with ZNF703 in a dose-dependent manner, promotes its polyubiquitination, and induces its proteasomal degradation; PARK2 re-expression reduces ZNF703 levels, decreases Cyclin D1/E1, and causes G1 cell cycle arrest in high-grade serous ovarian cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibition, overexpression/knockdown in cell lines, xenograft tumor model","journal":"Medical oncology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical reconstitution of ubiquitination, co-IP, in vivo xenograft validation, multiple orthogonal methods in single rigorous study","pmids":["39043895"],"is_preprint":false},{"year":2018,"finding":"ZNF703 knockdown in papillary thyroid cancer K1 cells downregulates E2F1 and MMP9 protein expression and enhances p27 protein expression, indicating ZNF703 regulates these downstream effectors independently of BRAF V600E.","method":"siRNA knockdown in K1 cell line, Western blotting for downstream targets","journal":"Pathology oncology research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single cell line, single method (Western blot), no direct binding or mechanistic validation","pmids":["30361900"],"is_preprint":false}],"current_model":"ZNF703/NLZ1 is a transcriptional repressor of the NET/NLZ zinc-finger family that requires HDAC activity and its Buttonhead domain for repression; it forms a nuclear complex with Groucho co-repressors, DCAF7, PHB2, and NCOR2, and directly binds promoter/enhancer sequences to repress targets including E-cadherin and activate others including PEA15 and linc-UBC1; its nuclear localization is facilitated by HE4 interaction; it modulates TGFβ, Wnt, Akt/mTOR, and MEK/ERK signaling pathways; it promotes luminal progenitor expansion and p120-catenin isoform switching to drive metastasis; and its protein levels are controlled by PARK2-mediated polyubiquitination and proteasomal degradation, which restrains G1/S progression."},"narrative":{"mechanistic_narrative":"ZNF703 (NLZ1/Zeppo1), a member of the NET/NLZ zinc-finger family, is a context-dependent transcriptional regulator that patterns development and drives epithelial tumorigenesis by controlling target gene expression [PMID:21317240, PMID:19014486]. Its core repressive activity requires histone deacetylase function and promotes histone deacetylation at target promoters, and it complexes with Groucho co-repressors to silence targets such as E-cadherin while attenuating Wnt and TGFβ reporter activity in mammary epithelial cells [PMID:21317240, PMID:19014486]. Structure-function analysis maps repression to the conserved Buttonhead domain rather than the Groucho-interaction domain, and identifies domains needed for proper nuclear localization [PMID:22886885, PMID:31164691]. In tumor cells ZNF703 also acts as a sequence-specific activator: it directly binds the PEA15 enhancer to induce its expression, with nuclear translocation facilitated by interaction with HE4 [PMID:33246486]. During development, ZNF703 functions downstream of Pax3/Zic1 and Foxj1a/Wnt signaling to control hindbrain patterning, neural crest formation, and motile ciliogenesis [PMID:26327644, PMID:29086464]. Its protein abundance is restrained by the E3 ligase PARK2, which polyubiquitinates ZNF703 and targets it for proteasomal degradation, lowering Cyclin D1/E1 and enforcing G1 arrest [PMID:39043895].","teleology":[{"year":2008,"claim":"Established that NLZ1/ZNF703 is a transcriptional repressor and defined the biochemical requirement for its silencing activity, answering how it represses targets.","evidence":"Luciferase reporters across cell lines, pharmacological HDAC inhibition, transgenic zebrafish ChIP for histone acetylation, and domain-deletion analysis","pmids":["19014486"],"confidence":"High","gaps":["Direct genomic targets in vivo not identified","Which HDAC complex is recruited not resolved"]},{"year":2011,"claim":"Linked ZNF703 to breast cancer by showing it complexes with Groucho to repress E-cadherin and dampen Wnt/TGFβ reporters, framing it as a metastasis-promoting repressor.","evidence":"Reporter assays, co-IP with Groucho, knockdown/overexpression in cell lines and a mouse breast cancer metastasis model","pmids":["21317240"],"confidence":"High","gaps":["Direct vs indirect binding at the E-cadherin promoter not distinguished","Whether Groucho is required for all targets unclear"]},{"year":2011,"claim":"Defined the nuclear protein environment of ZNF703 by isolating a complex with DCAF7, PHB2, and NCOR2 and connected its overexpression to luminal/stem programs and progenitor expansion.","evidence":"Mass spectrometry/co-IP of the nuclear complex plus expression profiling and colony-forming assays in luminal breast cancer and normal breast epithelial cells","pmids":["21328542","21337521"],"confidence":"Medium","gaps":["Functional roles of individual complex members not dissected","Direct target genes downstream of ER/E2F1 not validated by binding"]},{"year":2011,"claim":"Connected ZNF703 to the actin/adhesion machinery by showing it promotes the metastasis-associated p120-catenin isoform 1 and alters p120 localization on ECM contact.","evidence":"Overexpression/knockdown in mammary epithelial cells with immunofluorescence and Western blotting","pmids":["21317240"],"confidence":"Medium","gaps":["Mechanism of isoform switching not defined","Direct transcriptional control of p120 splicing not shown"]},{"year":2013,"claim":"Extended ZNF703 signaling output to Akt/mTOR activation and ERα downregulation, providing a route to endocrine-therapy resistance.","evidence":"Overexpression/siRNA in breast cancer lines, Western blotting of pathway components, viability assays with mTOR inhibitor + tamoxifen","pmids":["23991038"],"confidence":"Medium","gaps":["Whether Akt/mTOR activation is a direct transcriptional consequence unknown","Single lab, in vitro"]},{"year":2013,"claim":"Resolved the domain architecture, assigning subcellular distribution and repression to specific conserved domains and showing the Groucho-interaction domain is dispensable for Groucho binding.","evidence":"Domain-deletion mutants with localization imaging, reporter assays, and co-IP","pmids":["22886885"],"confidence":"Medium","gaps":["No structural model of the domains","Residue-level determinants of nuclear targeting not mapped"]},{"year":2017,"claim":"Placed Znf703 in a developmental regulatory hierarchy, acting downstream of Pax3/Zic1 to repress posterior hindbrain genes and control neural crest formation.","evidence":"Morpholino knockdown and overexpression in Xenopus, microarray target identification, in situ hybridization","pmids":["29086464"],"confidence":"Medium","gaps":["Direct hindbrain target promoters not identified","Mammalian relevance not tested"]},{"year":2015,"claim":"Demonstrated a Wnt-integrated role in motile ciliogenesis, positioning Nlz1 downstream of Foxj1a/canonical Wnt and as a positive regulator of non-canonical Wnt11 signaling.","evidence":"Zebrafish morpholino knockdown with epistasis analysis against Foxj1a and Wnt pathway components","pmids":["26327644"],"confidence":"Medium","gaps":["Transcriptional targets driving cilia formation unknown","Morpholino-based knockdown without genetic mutant confirmation"]},{"year":2019,"claim":"Pinpointed the Buttonhead domain (not the Groucho-repression domain) as the determinant of repression required for mesoderm, neural crest, and placode development.","evidence":"Xenopus overexpression/knockdown with domain mutant analysis and in situ hybridization","pmids":["31164691"],"confidence":"Medium","gaps":["Biochemical partner engaged by the Buttonhead domain unknown","Mechanism of RAR/Wnt induction of Znf703 not defined"]},{"year":2020,"claim":"Identified direct DNA-binding activator function and a nuclear-import regulator: ZNF703 binds the PEA15 enhancer to activate transcription, with HE4 promoting its nuclear translocation.","evidence":"ChIP-seq, ChIP-PCR, dual-luciferase reporter, co-IP, immunofluorescence co-localization, and xenograft model in ovarian cancer","pmids":["33246486"],"confidence":"High","gaps":["Determinants distinguishing activated vs repressed targets unclear","Whether HE4 regulates ZNF703 in other tissues unknown"]},{"year":2020,"claim":"Broadened the activator repertoire to long non-coding RNA loci, showing promoter binding and transcriptional activation of LINC00460 and linc-UBC1.","evidence":"ChIP/RIP assays, JASPAR prediction, dual-luciferase reporters, and rescue experiments in ovarian cancer and glioma cells","pmids":["32382355","32271436"],"confidence":"Medium","gaps":["linc-UBC1 binding rests on a single low-resolution assay (RIP + luciferase)","Direct vs indirect promoter occupancy not fully separated"]},{"year":2024,"claim":"Defined post-translational control of ZNF703 abundance, showing PARK2 ubiquitinates and degrades it to restrain G1/S progression via Cyclin D1/E1.","evidence":"Co-IP, in vitro ubiquitination assay, proteasome inhibition, overexpression/knockdown, and xenograft model in high-grade serous ovarian cancer","pmids":["39043895"],"confidence":"High","gaps":["Ubiquitinated lysine residues not mapped","Upstream signals regulating PARK2-ZNF703 axis unknown"]},{"year":null,"claim":"How ZNF703 switches between Groucho/HDAC-dependent repression and sequence-specific activation, and what selects its genomic targets, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying DNA-binding motif or rule for activation vs repression","No structural data on DNA engagement","Mammalian developmental targets largely undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,11]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[11,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,7,11]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,9,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[14]}],"complexes":["Groucho/TLE co-repressor complex","DCAF7-PHB2-NCOR2 nuclear complex"],"partners":["TLE/GROUCHO","DCAF7","PHB2","NCOR2","HE4","PARK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H7S9","full_name":"Zinc finger protein 703","aliases":["Zinc finger elbow-related proline domain protein 1"],"length_aa":590,"mass_kda":58.2,"function":"Transcriptional corepressor which does not bind directly to DNA and may regulate transcription through recruitment of histone deacetylases to gene promoters. Regulates cell adhesion, migration and proliferation. May be required for segmental gene expression during hindbrain development","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9H7S9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZNF703","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ERG28","stoichiometry":0.2},{"gene":"PHAX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZNF703","total_profiled":1310},"omim":[{"mim_id":"617045","title":"ZINC FINGER PROTEIN 703; ZNF703","url":"https://www.omim.org/entry/617045"},{"mim_id":"613902","title":"ZINC FINGER PROTEIN 503; ZNF503","url":"https://www.omim.org/entry/613902"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":104.7}],"url":"https://www.proteinatlas.org/search/ZNF703"},"hgnc":{"alias_symbol":["FLJ14299","ZNF503L","NLZ1","Zpo1","ZEPPO1"],"prev_symbol":[]},"alphafold":{"accession":"Q9H7S9","domains":[{"cath_id":"3.30.160","chopping":"457-485","consensus_level":"medium","plddt":89.1497,"start":457,"end":485}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7S9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7S9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7S9-F1-predicted_aligned_error_v6.png","plddt_mean":50.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZNF703","jax_strain_url":"https://www.jax.org/strain/search?query=ZNF703"},"sequence":{"accession":"Q9H7S9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H7S9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H7S9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7S9"}},"corpus_meta":[{"pmid":"25742952","id":"PMC_25742952","title":"The long noncoding RNA SPRY4-IT1 increases the proliferation of human breast cancer cells by upregulating ZNF703 expression.","date":"2015","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25742952","citation_count":140,"is_preprint":false},{"pmid":"21337521","id":"PMC_21337521","title":"ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium.","date":"2011","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21337521","citation_count":114,"is_preprint":false},{"pmid":"21328542","id":"PMC_21328542","title":"ZNF703 gene amplification at 8p12 specifies luminal B breast cancer.","date":"2011","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21328542","citation_count":102,"is_preprint":false},{"pmid":"21317240","id":"PMC_21317240","title":"Zeppo1 is a novel metastasis promoter that represses E-cadherin expression and regulates p120-catenin isoform 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proliferation, migration, and invasion of gastric cancer cells by regulating ZNF703 via sponging miR-4739.","date":"2021","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/33847425","citation_count":22,"is_preprint":false},{"pmid":"33488122","id":"PMC_33488122","title":"MiR-491-5p, as a Tumor Suppressor, Prevents Migration and Invasion of Breast Cancer by Targeting ZNF-703 to Regulate AKT/mTOR Pathway.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33488122","citation_count":22,"is_preprint":false},{"pmid":"32275336","id":"PMC_32275336","title":"USF1-induced overexpression of long noncoding RNA WDFY3-AS2 promotes lung adenocarcinoma progression via targeting miR-491-5p/ZNF703 axis.","date":"2020","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/32275336","citation_count":21,"is_preprint":false},{"pmid":"22886885","id":"PMC_22886885","title":"Characterization of human NLZ1/ZNF703 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/32382355","citation_count":6,"is_preprint":false},{"pmid":"37514116","id":"PMC_37514116","title":"ZNF703 mRNA-Targeting Antisense Oligonucleotide Blocks Cell Proliferation and Induces Apoptosis in Breast Cancer Cell Lines.","date":"2023","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/37514116","citation_count":4,"is_preprint":false},{"pmid":"32271436","id":"PMC_32271436","title":"Transcription factor ZNF703 activates linc-UBC1 to stimulate the progression of glioma.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32271436","citation_count":4,"is_preprint":false},{"pmid":"37810156","id":"PMC_37810156","title":"Insights into the pleiotropic roles of ZNF703 in cancer.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37810156","citation_count":3,"is_preprint":false},{"pmid":"39828065","id":"PMC_39828065","title":"ZNF703 promotes Triple-Negative breast cancer cell progression and in combination with STK11 predicts disease recurrence (ZS -TNBC Model).","date":"2025","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/39828065","citation_count":2,"is_preprint":false},{"pmid":"39043895","id":"PMC_39043895","title":"PARK2 suppresses the proliferation of high-grade serous ovarian carcinoma via inducing the proteasomal degradation of ZNF703.","date":"2024","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/39043895","citation_count":1,"is_preprint":false},{"pmid":"41023871","id":"PMC_41023871","title":"Pan-cancer analysis of the oncogenic role of ZNF703 in regulating tumor immunity.","date":"2025","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41023871","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16848,"output_tokens":3435,"usd":0.051034,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10993,"output_tokens":3722,"usd":0.074008,"stage2_stop_reason":"end_turn"},"total_usd":0.125042,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"ZNF703 (Zeppo1) complexes with Groucho co-repressor and represses E-cadherin transcription, as well as Wnt and TGFβ reporter expression, in mammary epithelial cells.\",\n      \"method\": \"Transcriptional reporter assays, co-immunoprecipitation, knockdown/overexpression in cell lines and mouse breast cancer model\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional data (reporter assays + co-IP with Groucho), supported by in vivo mouse metastasis model with defined molecular readouts\",\n      \"pmids\": [\"21317240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZNF703 is a co-factor of a nuclear complex comprising DCAF7, PHB2, and NCOR2, identified by mass spectrometry in luminal breast cancer cells.\",\n      \"method\": \"Mass spectrometry/co-immunoprecipitation of ZNF703-containing nuclear complex\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mass spectrometry identification in single study, limited functional follow-up on individual complex members\",\n      \"pmids\": [\"21328542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZNF703 overexpression activates stem cell-related gene expression and is implicated in regulation of ER and E2F1 transcription factors in luminal breast cancer cells.\",\n      \"method\": \"Overexpression in MCF7 cells with gene expression profiling\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, gene expression changes after overexpression without direct binding or mechanistic validation\",\n      \"pmids\": [\"21328542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZNF703 overexpression in MCF7 cells modifies TGFβ effects on proliferation, and overexpression in normal human breast epithelial cells enhances luminal progenitor colony-forming frequency.\",\n      \"method\": \"Overexpression and knockdown in cell lines, in vitro colony-forming assays\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in single lab, two orthogonal readouts (proliferation and colony forming)\",\n      \"pmids\": [\"21337521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZNF703 (Zeppo1) promotes expression of metastasis-associated p120-catenin isoform 1 and alters p120-catenin localization upon cell contact with extracellular matrix.\",\n      \"method\": \"Overexpression/knockdown in mammary epithelial cells with immunofluorescence and Western blotting\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, two orthogonal methods in single lab\",\n      \"pmids\": [\"21317240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Nlz1/Znf703 acts as a transcriptional repressor requiring histone deacetylase (HDAC) activity; repression was demonstrated in cell-based reporter assays and in developing zebrafish embryos, and Nlz1 promotes histone deacetylation at target promoters.\",\n      \"method\": \"Luciferase reporter assays (4 cell lines), pharmacological HDAC inhibition, transgenic zebrafish reporter line with ChIP for histone acetylation, structure-function (domain deletion) analysis\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (reporter assay, pharmacological inhibition, ChIP in vivo, structure-function), replicated across multiple cell lines and in zebrafish\",\n      \"pmids\": [\"19014486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ZNF703 overexpression in MCF-7 cells activates the Akt/mTOR signaling pathway and downregulates ERα, contributing to tamoxifen resistance; mTOR inhibition combined with tamoxifen overcomes this resistance in ZNF703-overexpressing cells.\",\n      \"method\": \"Overexpression and siRNA knockdown in breast cancer cell lines, Western blotting for pathway components, cell viability assays with drug treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway activation confirmed by Western blot and rescue with mTOR inhibitor, single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"23991038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human NLZ1/ZNF703 contains six evolutionarily conserved domains, three specific to NET proteins; specific domains are necessary for proper subcellular distribution and transcriptional repression, but the Groucho-interaction domain is not required for interaction with Groucho co-repressors.\",\n      \"method\": \"Domain deletion mutant analysis, subcellular localization imaging, transcriptional reporter assays, co-immunoprecipitation\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function analysis with multiple domain mutants and functional readouts in single lab\",\n      \"pmids\": [\"22886885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"nlz1/Znf703 is required for ciliogenesis in zebrafish: morpholino knockdown reduces cilia number in Kupffer's vesicle, pronephros, and neural floorplate; Nlz1 acts downstream of Foxj1a and Wnt8a/canonical Wnt signaling and positively regulates Wnt11/non-canonical Wnt signaling to promote motile cilia formation.\",\n      \"method\": \"Morpholino-mediated knockdown in zebrafish, epistasis analysis with Foxj1a and Wnt pathway components, in vitro and in vivo assays\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in zebrafish with defined pathway placement, single lab\",\n      \"pmids\": [\"26327644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Znf703/Nlz1 acts downstream of Pax3 and Zic1 in Xenopus to repress posterior hindbrain gene expression and regulate neural crest formation; its transcriptional repressor activity is critical for hindbrain patterning.\",\n      \"method\": \"Morpholino knockdown and overexpression in Xenopus, microarray-based identification as Pax3/Zic1 target, in situ hybridization for segmental gene markers\",\n      \"journal\": \"Genesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in Xenopus, two perturbation directions (knockdown and overexpression), single lab\",\n      \"pmids\": [\"29086464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Znf703 is an RAR- and Wnt-inducible transcription factor; its Buttonhead domain (not the Groucho-repression domain) is required for transcriptional repression affecting mesoderm, neural crest, and placode development in Xenopus.\",\n      \"method\": \"Overexpression and knockdown in Xenopus, domain mutant analysis (Groucho-repression domain mutation vs. Buttonhead domain mutation), in situ hybridization\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function with domain mutations in vivo, single lab\",\n      \"pmids\": [\"31164691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZNF703 interacts with HE4 protein, and HE4 promotes nuclear translocation of ZNF703; ZNF703 directly binds the enhancer region of PEA15 to promote PEA15 transcription in ovarian cancer cells.\",\n      \"method\": \"Immunofluorescence co-localization, co-immunoprecipitation, ChIP-sequencing, dual luciferase reporter assay, ChIP-PCR, in vivo xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including ChIP-seq, co-IP, reporter assay, and in vivo validation in single rigorous study\",\n      \"pmids\": [\"33246486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZNF703 acts as a transcription factor that binds to the LINC00460 promoter region to activate its transcription in ovarian cancer cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) assay, JASPAR database prediction, rescue experiments\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP assay confirms binding, single lab, single method for the binding claim\",\n      \"pmids\": [\"32382355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZNF703 transcriptionally activates linc-UBC1 by binding to its promoter region in glioma cells, promoting proliferation and invasion.\",\n      \"method\": \"RNA binding protein immunoprecipitation (RIP), dual-luciferase reporter assay, rescue experiments\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP and luciferase assay in single lab, limited mechanistic resolution\",\n      \"pmids\": [\"32271436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The E3 ubiquitin ligase PARK2 interacts with ZNF703 in a dose-dependent manner, promotes its polyubiquitination, and induces its proteasomal degradation; PARK2 re-expression reduces ZNF703 levels, decreases Cyclin D1/E1, and causes G1 cell cycle arrest in high-grade serous ovarian cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibition, overexpression/knockdown in cell lines, xenograft tumor model\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical reconstitution of ubiquitination, co-IP, in vivo xenograft validation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"39043895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZNF703 knockdown in papillary thyroid cancer K1 cells downregulates E2F1 and MMP9 protein expression and enhances p27 protein expression, indicating ZNF703 regulates these downstream effectors independently of BRAF V600E.\",\n      \"method\": \"siRNA knockdown in K1 cell line, Western blotting for downstream targets\",\n      \"journal\": \"Pathology oncology research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single cell line, single method (Western blot), no direct binding or mechanistic validation\",\n      \"pmids\": [\"30361900\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZNF703/NLZ1 is a transcriptional repressor of the NET/NLZ zinc-finger family that requires HDAC activity and its Buttonhead domain for repression; it forms a nuclear complex with Groucho co-repressors, DCAF7, PHB2, and NCOR2, and directly binds promoter/enhancer sequences to repress targets including E-cadherin and activate others including PEA15 and linc-UBC1; its nuclear localization is facilitated by HE4 interaction; it modulates TGFβ, Wnt, Akt/mTOR, and MEK/ERK signaling pathways; it promotes luminal progenitor expansion and p120-catenin isoform switching to drive metastasis; and its protein levels are controlled by PARK2-mediated polyubiquitination and proteasomal degradation, which restrains G1/S progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZNF703 (NLZ1/Zeppo1), a member of the NET/NLZ zinc-finger family, is a context-dependent transcriptional regulator that patterns development and drives epithelial tumorigenesis by controlling target gene expression [#0, #5]. Its core repressive activity requires histone deacetylase function and promotes histone deacetylation at target promoters, and it complexes with Groucho co-repressors to silence targets such as E-cadherin while attenuating Wnt and TGFβ reporter activity in mammary epithelial cells [#0, #5]. Structure-function analysis maps repression to the conserved Buttonhead domain rather than the Groucho-interaction domain, and identifies domains needed for proper nuclear localization [#7, #10]. In tumor cells ZNF703 also acts as a sequence-specific activator: it directly binds the PEA15 enhancer to induce its expression, with nuclear translocation facilitated by interaction with HE4 [#11]. During development, ZNF703 functions downstream of Pax3/Zic1 and Foxj1a/Wnt signaling to control hindbrain patterning, neural crest formation, and motile ciliogenesis [#8, #9]. Its protein abundance is restrained by the E3 ligase PARK2, which polyubiquitinates ZNF703 and targets it for proteasomal degradation, lowering Cyclin D1/E1 and enforcing G1 arrest [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that NLZ1/ZNF703 is a transcriptional repressor and defined the biochemical requirement for its silencing activity, answering how it represses targets.\",\n      \"evidence\": \"Luciferase reporters across cell lines, pharmacological HDAC inhibition, transgenic zebrafish ChIP for histone acetylation, and domain-deletion analysis\",\n      \"pmids\": [\"19014486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct genomic targets in vivo not identified\", \"Which HDAC complex is recruited not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked ZNF703 to breast cancer by showing it complexes with Groucho to repress E-cadherin and dampen Wnt/TGFβ reporters, framing it as a metastasis-promoting repressor.\",\n      \"evidence\": \"Reporter assays, co-IP with Groucho, knockdown/overexpression in cell lines and a mouse breast cancer metastasis model\",\n      \"pmids\": [\"21317240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect binding at the E-cadherin promoter not distinguished\", \"Whether Groucho is required for all targets unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the nuclear protein environment of ZNF703 by isolating a complex with DCAF7, PHB2, and NCOR2 and connected its overexpression to luminal/stem programs and progenitor expansion.\",\n      \"evidence\": \"Mass spectrometry/co-IP of the nuclear complex plus expression profiling and colony-forming assays in luminal breast cancer and normal breast epithelial cells\",\n      \"pmids\": [\"21328542\", \"21337521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional roles of individual complex members not dissected\", \"Direct target genes downstream of ER/E2F1 not validated by binding\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected ZNF703 to the actin/adhesion machinery by showing it promotes the metastasis-associated p120-catenin isoform 1 and alters p120 localization on ECM contact.\",\n      \"evidence\": \"Overexpression/knockdown in mammary epithelial cells with immunofluorescence and Western blotting\",\n      \"pmids\": [\"21317240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of isoform switching not defined\", \"Direct transcriptional control of p120 splicing not shown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended ZNF703 signaling output to Akt/mTOR activation and ERα downregulation, providing a route to endocrine-therapy resistance.\",\n      \"evidence\": \"Overexpression/siRNA in breast cancer lines, Western blotting of pathway components, viability assays with mTOR inhibitor + tamoxifen\",\n      \"pmids\": [\"23991038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Akt/mTOR activation is a direct transcriptional consequence unknown\", \"Single lab, in vitro\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the domain architecture, assigning subcellular distribution and repression to specific conserved domains and showing the Groucho-interaction domain is dispensable for Groucho binding.\",\n      \"evidence\": \"Domain-deletion mutants with localization imaging, reporter assays, and co-IP\",\n      \"pmids\": [\"22886885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the domains\", \"Residue-level determinants of nuclear targeting not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed Znf703 in a developmental regulatory hierarchy, acting downstream of Pax3/Zic1 to repress posterior hindbrain genes and control neural crest formation.\",\n      \"evidence\": \"Morpholino knockdown and overexpression in Xenopus, microarray target identification, in situ hybridization\",\n      \"pmids\": [\"29086464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct hindbrain target promoters not identified\", \"Mammalian relevance not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated a Wnt-integrated role in motile ciliogenesis, positioning Nlz1 downstream of Foxj1a/canonical Wnt and as a positive regulator of non-canonical Wnt11 signaling.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with epistasis analysis against Foxj1a and Wnt pathway components\",\n      \"pmids\": [\"26327644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional targets driving cilia formation unknown\", \"Morpholino-based knockdown without genetic mutant confirmation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pinpointed the Buttonhead domain (not the Groucho-repression domain) as the determinant of repression required for mesoderm, neural crest, and placode development.\",\n      \"evidence\": \"Xenopus overexpression/knockdown with domain mutant analysis and in situ hybridization\",\n      \"pmids\": [\"31164691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical partner engaged by the Buttonhead domain unknown\", \"Mechanism of RAR/Wnt induction of Znf703 not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified direct DNA-binding activator function and a nuclear-import regulator: ZNF703 binds the PEA15 enhancer to activate transcription, with HE4 promoting its nuclear translocation.\",\n      \"evidence\": \"ChIP-seq, ChIP-PCR, dual-luciferase reporter, co-IP, immunofluorescence co-localization, and xenograft model in ovarian cancer\",\n      \"pmids\": [\"33246486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants distinguishing activated vs repressed targets unclear\", \"Whether HE4 regulates ZNF703 in other tissues unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadened the activator repertoire to long non-coding RNA loci, showing promoter binding and transcriptional activation of LINC00460 and linc-UBC1.\",\n      \"evidence\": \"ChIP/RIP assays, JASPAR prediction, dual-luciferase reporters, and rescue experiments in ovarian cancer and glioma cells\",\n      \"pmids\": [\"32382355\", \"32271436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"linc-UBC1 binding rests on a single low-resolution assay (RIP + luciferase)\", \"Direct vs indirect promoter occupancy not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined post-translational control of ZNF703 abundance, showing PARK2 ubiquitinates and degrades it to restrain G1/S progression via Cyclin D1/E1.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination assay, proteasome inhibition, overexpression/knockdown, and xenograft model in high-grade serous ovarian cancer\",\n      \"pmids\": [\"39043895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitinated lysine residues not mapped\", \"Upstream signals regulating PARK2-ZNF703 axis unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZNF703 switches between Groucho/HDAC-dependent repression and sequence-specific activation, and what selects its genomic targets, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying DNA-binding motif or rule for activation vs repression\", \"No structural data on DNA engagement\", \"Mammalian developmental targets largely undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 11]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 7, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 9, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\"Groucho/TLE co-repressor complex\", \"DCAF7-PHB2-NCOR2 nuclear complex\"],\n    \"partners\": [\"TLE/Groucho\", \"DCAF7\", \"PHB2\", \"NCOR2\", \"HE4\", \"PARK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}