{"gene":"LDOC1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1999,"finding":"LDOC1 encodes a nuclear protein containing a leucine zipper-like motif at the N-terminal region and a proline-rich SH3-binding domain; EGFP-LDOC1 fusion protein localizes to the nucleus.","method":"EGFP fusion protein localization assay, Northern blot, chromosomal mapping","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct subcellular localization by fluorescence imaging, single lab","pmids":["10403563"],"is_preprint":false},{"year":2003,"finding":"LDOC1 inhibits NF-κB transcriptional activity; transient LDOC1 expression suppressed NF-κB reporter activity induced by MEKK1, TNF-α, or PMA in BxPC-3 pancreatic cancer cells, and stable LDOC1 expression enhanced TNF-α/PMA-induced antiproliferative/apoptotic effects.","method":"NF-κB luciferase reporter assay, stable transfection, cell viability assay","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (reporter assay, dose-response, stable transfection), replicated across stimuli","pmids":["12712434"],"is_preprint":false},{"year":2005,"finding":"LDOC1 interacts directly with the transcription factor MZF-1, and MZF-1 enhances LDOC1-induced apoptosis; LDOC1 overexpression causes phosphatidylserine externalization, loss of mitochondrial membrane potential, and activates both caspase-3-dependent and -independent apoptotic pathways.","method":"Co-immunoprecipitation/protein interaction assay, flow cytometry (annexin V, JC-1 dye), caspase activity assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding assay with functional apoptosis readout, single lab","pmids":["15670815"],"is_preprint":false},{"year":2005,"finding":"WAVE3 binds directly to LDOC1 via the WAVE3 verprolin homology domain; WAVE3 expression induces translocation of LDOC1 from the nucleus to the cytoplasm and inhibits LDOC1-induced apoptosis; LDOC1-induced apoptosis is accompanied by increased p53 protein (not transcript), suggesting LDOC1 inhibits p53 degradation.","method":"Direct binding assay (pulldown), subcellular localization (fluorescence microscopy), apoptosis assay, p53 protein/mRNA quantification","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding domain mapped, localization shift demonstrated, functional apoptosis consequence shown, multiple orthogonal methods","pmids":["16272576"],"is_preprint":false},{"year":2013,"finding":"Restored expression of BEX1 and/or LDOC1 suppresses NF-κB signaling in oral squamous cell carcinoma cells, associated with decreased p50 and p65 expression, and inhibits growth in vitro and in vivo.","method":"Ectopic expression, NF-κB pathway analysis (Western blot for p50/p65), in vitro and in vivo growth assays","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo experiments with defined pathway readout, single lab","pmids":["23362108"],"is_preprint":false},{"year":2014,"finding":"Sirh7/Ldoc1 knockout in mice causes abnormal trophoblast giant cell differentiation/maturation leading to overproduction of placental progesterone (P4) and placental lactogen 1 (PL1), and delayed parturition, establishing LDOC1 as a regulator of placental endocrine function.","method":"Knockout mouse model, hormone measurement (P4, PL1), histological analysis of placenta","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — clean KO model with specific endocrine and developmental phenotypic readouts, in vivo","pmids":["25468940"],"is_preprint":false},{"year":2015,"finding":"LDOC1 loss promotes proliferation and clonogenicity of untransformed oral cells; cigarette smoke condensate (CSC) induces LDOC1 promoter hypermethylation via increased nuclear DNMT1 and DNMT3A, silencing LDOC1 expression.","method":"CSC treatment, quantitative methylation-specific PCR, DNMT1/DNMT3A nuclear accumulation assay, knockdown proliferation/clonogenicity assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic link between CSC, DNMTs, methylation, and functional loss-of-function phenotype, single lab","pmids":["26317789"],"is_preprint":false},{"year":2015,"finding":"LDOC1 overexpression in papillary thyroid carcinoma TPC-1 cells suppresses NF-κB activation (reducing p65 nuclear translocation, IκBα degradation, c-Myc, and Bcl-xL), inhibits proliferation, induces apoptosis (increasing Bax), and restores responsiveness to TGF-β1 antiproliferative signaling.","method":"Lentiviral LDOC1 overexpression, NF-κB luciferase reporter assay, Western blot (p65, IκBα, c-Myc, Bax, Bcl-xL), flow cytometry, cell cycle analysis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing NF-κB as mechanistic node, single lab","pmids":["26637328"],"is_preprint":false},{"year":2016,"finding":"LDOC1 interacts with GNL3L (a nucleolar GTPase) via protein-protein interaction; ectopic LDOC1 destabilizes endogenous GNL3L and down-modulates GNL3L-induced cell proliferation; GNL3L upregulates NF-κB-dependent transcriptional activity through p65, which is reversed by LDOC1 co-expression.","method":"Co-immunoprecipitation, ectopic expression/knockdown, NF-κB reporter assay, cell proliferation assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal interaction shown with functional NF-κB and proliferation consequences, single lab","pmids":["27764577"],"is_preprint":false},{"year":2017,"finding":"Stable knockdown of LDOC1 in ependymoma cell lines significantly increases transcription of RELA (v-rel/p65) and NF-κB target gene expression, including IL-6 secretion; demethylation of LDOC1 promoter by 5-AZA-DC restores LDOC1 expression and decreases IL-6 secretion.","method":"Stable shRNA knockdown, RT-PCR, ELISA (IL-6), demethylation treatment (5-AZA-DC), gene expression analysis","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined NF-κB/IL-6 pathway readout, epigenetic mechanism confirmed, single lab","pmids":["28510691"],"is_preprint":false},{"year":2019,"finding":"LDOC1 forms protein complexes with phospho-JAK2 (pJAK2) and E3 ubiquitin ligase LNX1; LDOC1 targets pJAK2 for ubiquitin-dependent proteasomal degradation, thereby inhibiting STAT3 activation; LDOC1 deficiency attenuates LNX1-pJAK2 interaction, leading to ineffective pJAK2 ubiquitination and STAT3 activation.","method":"Co-immunoprecipitation, immunofluorescence confocal microscopy, ubiquitination assay, in vivo xenograft with LDOC1 knockdown measuring pJAK2/pSTAT3","journal":"Cancers","confidence":"High","confidence_rationale":"Tier 1–2 — complex mechanism (IP, co-localization, ubiquitination assay, in vivo) with multiple orthogonal methods in single rigorous study","pmids":["30634502"],"is_preprint":false},{"year":2019,"finding":"miR-4532 secreted by AML cells via exosomes targets LDOC1 mRNA in hematopoietic stem cells; LDOC1 suppression activates the JAK2/STAT3 signaling pathway, inhibiting normal hematopoiesis; ectopic LDOC1 expression or miR-4532 inhibition restores CFU and reduces DKK1 and JAK2/STAT3 phosphorylation.","method":"Luciferase reporter (miR-4532 targeting LDOC1 3'UTR), exosome co-culture, gain/loss-of-function, Western blot (pJAK2, pSTAT3), CFU assay","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — direct target validation plus functional pathway readout, single lab","pmids":["31842997"],"is_preprint":false},{"year":2019,"finding":"LDOC1 expression decreases Wnt5a levels in osteosarcoma cells and inhibits cell migration and invasion in vitro and lung metastasis in vivo.","method":"Lentiviral LDOC1 expression, Transwell migration/invasion assay, qRT-PCR array, xenograft micro-CT imaging","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo with defined Wnt5a pathway readout, single lab","pmids":["28240050"],"is_preprint":false},{"year":2019,"finding":"LDOC1 expression downregulates the Wnt/β-catenin signaling pathway in colorectal cancer cells, reducing β-catenin nuclear localization, inhibiting proliferation and metastasis.","method":"Lentiviral overexpression, Western blot (β-catenin), immunofluorescence (β-catenin localization), Transwell assay, flow cytometry","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods linking LDOC1 to Wnt/β-catenin with subcellular readout, single lab","pmids":["31002361"],"is_preprint":false},{"year":2020,"finding":"LDOC1 deficiency increases PI3K/Akt activation upon Candida albicans stimulation, leading to inhibitory phosphorylation of GSK-3β at Ser9 by activated Akt, resulting in enhanced IL-1β production; constitutively active GSK-3β(S9A) mutant or PI3K/Akt inhibitors reverse this effect.","method":"Loss/gain-of-function LDOC1 manipulation, Western blot (pAkt, pGSK-3βS9), PI3K/Akt inhibitor treatment, constitutively active GSK-3β mutant expression, IL-1β ELISA","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway dissected with inhibitors and dominant-active mutant, single lab","pmids":["33120999"],"is_preprint":false},{"year":2024,"finding":"LINC01270 acts as a competing endogenous RNA (ceRNA) that sponges miR-326; miR-326 targets LDOC1 mRNA, so LINC01270 knockdown reduces LDOC1 expression, enhancing NF-κB activity and IL-6/IL-8/MCP-1 production; luciferase reporter assay confirmed LINC01270 overexpression suppresses NF-κB activation.","method":"siRNA knockdown, luciferase reporter assay, miRNA interactome analysis, synthetic RNA perturbation","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — ceRNA axis validated by multiple orthogonal methods with NF-κB functional readout, single lab","pmids":["39682774"],"is_preprint":false},{"year":2025,"finding":"LDOC1 interacts with histone H2B and H2Bub1 as well as with PSMA1 to promote their proteasomal degradation, limiting global H2Bub1 levels; LDOC1 knockdown causes loss of chromatin-bound H2Bub1 and enhanced chromatin compaction partially mediated through LDOC1-THAP12 interaction; LDOC1-H2Bub1 axis regulates metastasis-related genes (cytoskeletal remodeling, cell adhesion, EMT) and LDOC1 loss enhances TGF-β-induced epithelial-mesenchymal plasticity.","method":"Co-immunoprecipitation, proximity ligation assay, ChIP-seq, ATAC-seq, MNase digestion assay, transcriptomic profiling, immunofluorescence, functional migration/adhesion assays","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (IP, PLA, ChIP-seq, ATAC-seq, MNase) in single rigorous study establishing epigenetic mechanism","pmids":["41484780"],"is_preprint":false},{"year":2025,"finding":"In PFA1 ependymoma, H3K27me3 chromatin compaction at the LDOC1 locus silences LDOC1 expression; restoration of LDOC1 reduces NF-κB signaling, IL-6 secretion, and tumor cell proliferation; loss of LDOC1 is required for PFA tumor growth in vivo.","method":"ChIP (H3K27me3), lentiviral LDOC1 transduction, in vivo tumor competition assay, NF-κB signaling assay, IL-6 ELISA","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 — epigenetic mechanism and in vivo requirement established with multiple methods, single lab","pmids":["39901723"],"is_preprint":false}],"current_model":"LDOC1 is a nuclear leucine-zipper protein that functions as a tumor suppressor through multiple mechanistic arms: it directly inhibits NF-κB signaling (suppressing p65/p50 and downstream cytokines including IL-6), interacts with GNL3L to reduce p65-driven proliferation, forms a complex with pJAK2 and E3 ligase LNX1 to promote ubiquitin-dependent proteasomal degradation of pJAK2 (thereby blocking JAK2/STAT3 activation), suppresses PI3K/Akt/GSK-3β-mediated IL-1β production, and regulates chromatin accessibility by controlling H2B monoubiquitination levels through interaction with H2B, H2Bub1, PSMA1, and THAP12; additionally, LDOC1 is negatively regulated by WAVE3, which sequesters it from the nucleus to the cytoplasm, and by miRNAs (miR-4532, miR-326, miR-330-5p) delivered via exosomes or sponged by lncRNAs, while in the placenta LDOC1 regulates trophoblast giant cell differentiation and progesterone production."},"narrative":{"teleology":[{"year":1999,"claim":"The initial characterization of LDOC1 established it as a nuclear protein with a leucine-zipper-like motif and SH3-binding domain, providing the structural basis for subsequent interaction studies.","evidence":"EGFP fusion imaging and Northern blot in human cell lines","pmids":["10403563"],"confidence":"Medium","gaps":["No interaction partners or functional consequence identified","Localization confirmed only by overexpressed fusion protein"]},{"year":2003,"claim":"LDOC1 was shown to suppress NF-κB transcriptional activity and sensitize cancer cells to TNF-α/PMA-induced apoptosis, establishing NF-κB inhibition as its core tumor-suppressive mechanism.","evidence":"NF-κB luciferase reporter, stable transfection, and viability assays in BxPC-3 pancreatic cancer cells","pmids":["12712434"],"confidence":"High","gaps":["Molecular mechanism of NF-κB inhibition not defined","No loss-of-function validation"]},{"year":2005,"claim":"Two studies revealed that LDOC1 interacts with MZF-1 to potentiate apoptosis through mitochondrial and caspase pathways, and that WAVE3 sequesters LDOC1 from the nucleus to the cytoplasm to antagonize its pro-apoptotic function, establishing regulation of LDOC1 by subcellular relocalization.","evidence":"Co-immunoprecipitation, pulldown with domain mapping, fluorescence microscopy, annexin V/JC-1 flow cytometry","pmids":["15670815","16272576"],"confidence":"High","gaps":["Physiological relevance of WAVE3-LDOC1 axis in tumors not demonstrated","p53 stabilization mechanism not molecularly defined"]},{"year":2013,"claim":"Restoration of LDOC1 (with BEX1) in oral squamous cell carcinoma cells confirmed NF-κB suppression through reduced p50/p65 protein and demonstrated growth inhibition in vivo, extending the NF-κB axis to a second cancer type.","evidence":"Ectopic expression, Western blot for p50/p65, in vitro and xenograft growth assays","pmids":["23362108"],"confidence":"Medium","gaps":["Individual contribution of LDOC1 versus BEX1 not fully separated","Mechanism of p50/p65 protein reduction unclear"]},{"year":2014,"claim":"Knockout of Ldoc1 (Sirh7) in mice revealed its non-oncological role in trophoblast giant cell differentiation and placental endocrine control, demonstrating that LDOC1 restrains progesterone and PL1 production to ensure timely parturition.","evidence":"Ldoc1 knockout mouse, placental histology, P4 and PL1 hormone measurement","pmids":["25468940"],"confidence":"High","gaps":["Molecular targets of LDOC1 in trophoblasts not identified","Whether NF-κB or JAK2/STAT3 pathways are involved in placental phenotype is unknown"]},{"year":2015,"claim":"Cigarette smoke condensate was shown to silence LDOC1 via DNMT1/DNMT3A-mediated promoter hypermethylation, and LDOC1 loss promoted proliferation/clonogenicity, linking an environmental carcinogen to epigenetic LDOC1 inactivation.","evidence":"CSC treatment, methylation-specific PCR, DNMT nuclear accumulation, knockdown proliferation assays in oral keratinocytes","pmids":["26317789"],"confidence":"Medium","gaps":["Direct DNMT recruitment to LDOC1 promoter not shown by ChIP","Whether CSC-induced methylation is reversible in vivo is untested"]},{"year":2016,"claim":"Identification of GNL3L as a direct LDOC1 interactor established a mechanism by which LDOC1 destabilizes GNL3L and reverses GNL3L-driven NF-κB/p65 activation and proliferation.","evidence":"Co-immunoprecipitation, ectopic expression/knockdown, NF-κB reporter, proliferation assay","pmids":["27764577"],"confidence":"Medium","gaps":["Mechanism of GNL3L destabilization (proteasomal? transcriptional?) not defined","In vivo relevance not tested"]},{"year":2017,"claim":"Stable LDOC1 knockdown in ependymoma cells increased RELA transcription and IL-6 secretion, and demethylation restored LDOC1 expression, demonstrating that epigenetic LDOC1 silencing drives NF-κB-dependent cytokine production in brain tumors.","evidence":"Stable shRNA knockdown, ELISA for IL-6, 5-AZA-DC demethylation in ependymoma cell lines","pmids":["28510691"],"confidence":"Medium","gaps":["Whether LDOC1 directly regulates RELA transcription or acts indirectly is unknown","Single cell line system"]},{"year":2019,"claim":"LDOC1 was shown to bridge pJAK2 to the E3 ligase LNX1, promoting ubiquitin-dependent pJAK2 degradation and STAT3 inactivation, revealing an adaptor function in targeted protein turnover and a second major signaling axis suppressed by LDOC1.","evidence":"Co-immunoprecipitation, ubiquitination assay, confocal microscopy, in vivo xenograft with LDOC1 knockdown","pmids":["30634502"],"confidence":"High","gaps":["Structural basis of ternary complex formation unknown","Whether LDOC1 similarly directs degradation of other substrates is unexplored"]},{"year":2019,"claim":"Exosomal miR-4532 from AML cells was identified as a negative regulator of LDOC1 in hematopoietic stem cells, linking LDOC1 suppression to JAK2/STAT3-mediated disruption of normal hematopoiesis in the leukemic niche.","evidence":"Luciferase reporter for miR-4532–LDOC1 3′UTR, exosome co-culture, CFU assay, Western blot for pJAK2/pSTAT3","pmids":["31842997"],"confidence":"Medium","gaps":["In vivo validation of exosomal miR-4532 niche effect not performed","Whether LDOC1 is the sole relevant target of miR-4532 is unclear"]},{"year":2019,"claim":"LDOC1 was found to suppress Wnt/β-catenin signaling, reducing β-catenin nuclear localization and Wnt5a levels, broadening LDOC1's tumor-suppressive reach to a third major oncogenic pathway.","evidence":"Lentiviral overexpression, Western blot and immunofluorescence for β-catenin, Transwell assays, xenograft imaging in osteosarcoma and colorectal cancer cells","pmids":["28240050","31002361"],"confidence":"Medium","gaps":["Direct molecular mechanism linking LDOC1 to Wnt pathway components not identified","Relationship between Wnt suppression and NF-κB suppression unclear"]},{"year":2020,"claim":"LDOC1 deficiency was shown to enhance PI3K/Akt activation and inhibitory GSK-3β phosphorylation, leading to increased IL-1β production, establishing a PI3K/Akt/GSK-3β axis as another pathway restrained by LDOC1.","evidence":"Loss/gain-of-function, PI3K/Akt inhibitors, constitutively active GSK-3β(S9A) mutant, IL-1β ELISA upon Candida stimulation","pmids":["33120999"],"confidence":"Medium","gaps":["Direct target of LDOC1 in PI3K/Akt pathway not identified","Relevance to cancer versus innate immunity not delineated"]},{"year":2024,"claim":"The lncRNA LINC01270 was identified as a ceRNA sponging miR-326 to protect LDOC1 mRNA, establishing a second miRNA-based regulatory axis controlling LDOC1-dependent NF-κB suppression.","evidence":"siRNA knockdown, luciferase reporter, miRNA interactome analysis","pmids":["39682774"],"confidence":"Medium","gaps":["In vivo ceRNA axis validation lacking","Relative importance of miR-326 versus miR-4532 in LDOC1 regulation unknown"]},{"year":2025,"claim":"LDOC1 was revealed to regulate chromatin organization by interacting with H2B, H2Bub1, PSMA1, and THAP12 to control H2Bub1 levels, chromatin accessibility, and expression of metastasis-related genes, representing a fundamental epigenetic mechanism distinct from its signaling pathway functions.","evidence":"Co-immunoprecipitation, proximity ligation assay, ChIP-seq, ATAC-seq, MNase digestion, transcriptomics, migration/adhesion assays","pmids":["41484780"],"confidence":"High","gaps":["Whether H2Bub1 regulation underlies LDOC1's effects on NF-κB, JAK2/STAT3, and Wnt pathways is untested","Structural basis of LDOC1-H2Bub1 interaction unknown"]},{"year":2025,"claim":"H3K27me3-mediated silencing at the LDOC1 locus was shown to be required for PFA ependymoma growth, and LDOC1 restoration suppressed NF-κB/IL-6 and tumor growth in vivo, confirming LDOC1 as a bona fide tumor suppressor in this brain tumor.","evidence":"ChIP for H3K27me3, lentiviral LDOC1 restoration, in vivo tumor competition assay, IL-6 ELISA","pmids":["39901723"],"confidence":"Medium","gaps":["Whether H3K27me3 silencing is driven by EZH2 or other methyltransferases at LDOC1 not tested","Therapeutic strategies to restore LDOC1 in PFA not explored"]},{"year":null,"claim":"It remains unknown whether LDOC1's epigenetic function (H2Bub1 regulation) mechanistically underlies its suppression of NF-κB, JAK2/STAT3, PI3K/Akt, and Wnt/β-catenin signaling, or whether these represent independent parallel functions; no structural model of LDOC1 or its complexes exists.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of LDOC1 or any of its complexes determined","Hierarchy among multiple suppressed pathways unresolved","Physiological relevance of LDOC1 in non-cancer adult tissues beyond placenta unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,7,8,10,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,7]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,4,7,8,9,15,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,10,11,13,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,14,15]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5]}],"complexes":[],"partners":["WAVE3","MZF1","GNL3L","LNX1","JAK2","PSMA1","THAP12","H2BC1"],"other_free_text":[]},"mechanistic_narrative":"LDOC1 is a nuclear leucine-zipper protein that functions as a tumor suppressor by restraining NF-κB, JAK2/STAT3, PI3K/Akt, and Wnt/β-catenin signaling pathways and by regulating chromatin organization through control of histone H2B monoubiquitination. LDOC1 directly inhibits NF-κB transcriptional activity by suppressing p65/p50 expression and nuclear translocation, thereby reducing downstream cytokine production including IL-6 [PMID:12712434, PMID:28510691, PMID:26637328]; it also forms a ternary complex with phospho-JAK2 and the E3 ubiquitin ligase LNX1 to promote ubiquitin-dependent proteasomal degradation of pJAK2, blocking STAT3 activation [PMID:30634502]. LDOC1 interacts with histone H2B, H2Bub1, PSMA1, and THAP12 to limit global H2Bub1 levels and regulate chromatin accessibility at metastasis-related gene loci, and its loss enhances TGF-β-induced epithelial–mesenchymal plasticity [PMID:41484780]. In the placenta, LDOC1 knockout causes aberrant trophoblast giant cell differentiation and progesterone overproduction leading to delayed parturition [PMID:25468940]."},"prefetch_data":{"uniprot":{"accession":"O95751","full_name":"Protein LDOC1","aliases":["Leucine zipper protein down-regulated in cancer cells"],"length_aa":146,"mass_kda":17.0,"function":"May have an important role in the development and/or progression of some cancers","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O95751/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LDOC1","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":[],"url":"https://opencell.sf.czbiohub.org/search/LDOC1","total_profiled":1310},"omim":[{"mim_id":"300402","title":"LEUCINE ZIPPER, DOWNREGULATED IN CANCER 1; LDOC1","url":"https://www.omim.org/entry/300402"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":54.7}],"url":"https://www.proteinatlas.org/search/LDOC1"},"hgnc":{"alias_symbol":["Mar7","Mart7","SIRH7","RTL7"],"prev_symbol":["BCUR1"]},"alphafold":{"accession":"O95751","domains":[{"cath_id":"1.20.5","chopping":"2-45","consensus_level":"medium","plddt":94.107,"start":2,"end":45},{"cath_id":"1.10.1200","chopping":"62-130","consensus_level":"high","plddt":96.7025,"start":62,"end":130}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95751","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95751-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95751-F1-predicted_aligned_error_v6.png","plddt_mean":90.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LDOC1","jax_strain_url":"https://www.jax.org/strain/search?query=LDOC1"},"sequence":{"accession":"O95751","fasta_url":"https://rest.uniprot.org/uniprotkb/O95751.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95751/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95751"}},"corpus_meta":[{"pmid":"23362108","id":"PMC_23362108","title":"Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma.","date":"2013","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23362108","citation_count":79,"is_preprint":false},{"pmid":"12712434","id":"PMC_12712434","title":"Leucine-zipper protein, LDOC1, inhibits NF-kappaB activation and sensitizes pancreatic cancer cells to apoptosis.","date":"2003","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12712434","citation_count":65,"is_preprint":false},{"pmid":"10403563","id":"PMC_10403563","title":"Identification of a novel gene, LDOC1, down-regulated in cancer cell lines.","date":"1999","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/10403563","citation_count":64,"is_preprint":false},{"pmid":"25468940","id":"PMC_25468940","title":"Sirh7/Ldoc1 knockout mice exhibit placental P4 overproduction and delayed parturition.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25468940","citation_count":56,"is_preprint":false},{"pmid":"15670815","id":"PMC_15670815","title":"LDOC1, a novel MZF-1-interacting protein, induces apoptosis.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15670815","citation_count":38,"is_preprint":false},{"pmid":"31842997","id":"PMC_31842997","title":"Acute myeloid leukemia cells secrete microRNA-4532-containing exosomes to mediate normal hematopoiesis in hematopoietic stem cells by activating the LDOC1-dependent STAT3 signaling pathway.","date":"2019","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31842997","citation_count":38,"is_preprint":false},{"pmid":"26637328","id":"PMC_26637328","title":"LDOC1 inhibits proliferation and promotes apoptosis by repressing NF-κB activation in papillary thyroid carcinoma.","date":"2015","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/26637328","citation_count":35,"is_preprint":false},{"pmid":"31889905","id":"PMC_31889905","title":"HAND2-AS1 inhibits invasion and metastasis of cervical cancer cells via microRNA-330-5p-mediated LDOC1.","date":"2019","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/31889905","citation_count":30,"is_preprint":false},{"pmid":"27764577","id":"PMC_27764577","title":"Leucine Zipper Down-regulated in Cancer-1 (LDOC1) interacts with Guanine nucleotide binding protein-like 3-like (GNL3L) to modulate Nuclear Factor-kappa B (NF-κB) signaling during cell proliferation.","date":"2016","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/27764577","citation_count":28,"is_preprint":false},{"pmid":"30634502","id":"PMC_30634502","title":"Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/30634502","citation_count":22,"is_preprint":false},{"pmid":"28510691","id":"PMC_28510691","title":"NF-κB upregulation through epigenetic silencing of LDOC1 drives tumor biology and specific immunophenotype in Group A ependymoma.","date":"2017","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28510691","citation_count":20,"is_preprint":false},{"pmid":"26317789","id":"PMC_26317789","title":"LDOC1 silenced by cigarette exposure and involved in oral neoplastic transformation.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26317789","citation_count":19,"is_preprint":false},{"pmid":"24125169","id":"PMC_24125169","title":"Loss of LDOC1 expression by promoter methylation in cervical cancer cells.","date":"2013","source":"Cancer investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24125169","citation_count":18,"is_preprint":false},{"pmid":"16272576","id":"PMC_16272576","title":"WAVE3 functions as a negative regulator of LDOC1.","date":"2005","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16272576","citation_count":18,"is_preprint":false},{"pmid":"24554348","id":"PMC_24554348","title":"Epigenetic silencing of the LDOC1 tumor suppressor gene in ovarian cancer cells.","date":"2014","source":"Archives of gynecology and obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/24554348","citation_count":13,"is_preprint":false},{"pmid":"33120999","id":"PMC_33120999","title":"LDOC1 Suppresses Microbe-Induced Production of IL-1β in Human Normal and Cancerous Oral Cells through the PI3K/Akt/GSK-3β Axis.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33120999","citation_count":12,"is_preprint":false},{"pmid":"30993049","id":"PMC_30993049","title":"Salivary LDOC1 is a gender-difference biomarker of oral squamous cell carcinoma.","date":"2019","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/30993049","citation_count":6,"is_preprint":false},{"pmid":"37635478","id":"PMC_37635478","title":"Calycosin inhibits gemcitabine-resistant lung cancer cells proliferation through modulation of the LDOC1/GNL3L/NFκB.","date":"2023","source":"The Chinese journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37635478","citation_count":6,"is_preprint":false},{"pmid":"23942005","id":"PMC_23942005","title":"Overexpression of LDOC1 in human biliary epithelial cells inhibits apoptosis through NF-κB signaling.","date":"2013","source":"Journal of pediatric gastroenterology and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/23942005","citation_count":6,"is_preprint":false},{"pmid":"28240050","id":"PMC_28240050","title":"LDOC1 regulates Wnt5a expression and osteosarcoma cell metastasis and is correlated with the survival of osteosarcoma patients.","date":"2017","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28240050","citation_count":6,"is_preprint":false},{"pmid":"31002361","id":"PMC_31002361","title":"Effects of LDOC1 on colorectal cancer cells via downregulation of the Wnt/β-catenin signaling pathway.","date":"2019","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31002361","citation_count":5,"is_preprint":false},{"pmid":"31889386","id":"PMC_31889386","title":"LDOC1 is differentially expressed in thyroid cancer and display tumor-suppressive function in papillary thyroid carcinoma.","date":"2020","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/31889386","citation_count":3,"is_preprint":false},{"pmid":"39682774","id":"PMC_39682774","title":"LINC01270 Regulates the NF-κB-Mediated Pro-Inflammatory Response via the miR-326/LDOC1 Axis in THP-1 Cells.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/39682774","citation_count":2,"is_preprint":false},{"pmid":"41484780","id":"PMC_41484780","title":"LDOC1 connects histone H2B monoubiquitination to tumor cell plasticity in non-small cell lung cancer.","date":"2026","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/41484780","citation_count":0,"is_preprint":false},{"pmid":"39901723","id":"PMC_39901723","title":"Loss of LDOC1 by chromatin compaction in mesenchymal tumor cells is required for PFA1 ependymoma growth.","date":"2025","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39901723","citation_count":0,"is_preprint":false},{"pmid":"41828328","id":"PMC_41828328","title":"A Novel Role of the LINC01270/miR-326/LDOC1 Axis in Proinflammatory Response Regulation via STAT1 Modulation in THP-1 Cells.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41828328","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15375,"output_tokens":4505,"usd":0.05685},"stage2":{"model":"claude-opus-4-6","input_tokens":8104,"output_tokens":3906,"usd":0.207255},"total_usd":0.264105,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"LDOC1 encodes a nuclear protein containing a leucine zipper-like motif at the N-terminal region and a proline-rich SH3-binding domain; EGFP-LDOC1 fusion protein localizes to the nucleus.\",\n      \"method\": \"EGFP fusion protein localization assay, Northern blot, chromosomal mapping\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization by fluorescence imaging, single lab\",\n      \"pmids\": [\"10403563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LDOC1 inhibits NF-κB transcriptional activity; transient LDOC1 expression suppressed NF-κB reporter activity induced by MEKK1, TNF-α, or PMA in BxPC-3 pancreatic cancer cells, and stable LDOC1 expression enhanced TNF-α/PMA-induced antiproliferative/apoptotic effects.\",\n      \"method\": \"NF-κB luciferase reporter assay, stable transfection, cell viability assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter assay, dose-response, stable transfection), replicated across stimuli\",\n      \"pmids\": [\"12712434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LDOC1 interacts directly with the transcription factor MZF-1, and MZF-1 enhances LDOC1-induced apoptosis; LDOC1 overexpression causes phosphatidylserine externalization, loss of mitochondrial membrane potential, and activates both caspase-3-dependent and -independent apoptotic pathways.\",\n      \"method\": \"Co-immunoprecipitation/protein interaction assay, flow cytometry (annexin V, JC-1 dye), caspase activity assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay with functional apoptosis readout, single lab\",\n      \"pmids\": [\"15670815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"WAVE3 binds directly to LDOC1 via the WAVE3 verprolin homology domain; WAVE3 expression induces translocation of LDOC1 from the nucleus to the cytoplasm and inhibits LDOC1-induced apoptosis; LDOC1-induced apoptosis is accompanied by increased p53 protein (not transcript), suggesting LDOC1 inhibits p53 degradation.\",\n      \"method\": \"Direct binding assay (pulldown), subcellular localization (fluorescence microscopy), apoptosis assay, p53 protein/mRNA quantification\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding domain mapped, localization shift demonstrated, functional apoptosis consequence shown, multiple orthogonal methods\",\n      \"pmids\": [\"16272576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Restored expression of BEX1 and/or LDOC1 suppresses NF-κB signaling in oral squamous cell carcinoma cells, associated with decreased p50 and p65 expression, and inhibits growth in vitro and in vivo.\",\n      \"method\": \"Ectopic expression, NF-κB pathway analysis (Western blot for p50/p65), in vitro and in vivo growth assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo experiments with defined pathway readout, single lab\",\n      \"pmids\": [\"23362108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sirh7/Ldoc1 knockout in mice causes abnormal trophoblast giant cell differentiation/maturation leading to overproduction of placental progesterone (P4) and placental lactogen 1 (PL1), and delayed parturition, establishing LDOC1 as a regulator of placental endocrine function.\",\n      \"method\": \"Knockout mouse model, hormone measurement (P4, PL1), histological analysis of placenta\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO model with specific endocrine and developmental phenotypic readouts, in vivo\",\n      \"pmids\": [\"25468940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LDOC1 loss promotes proliferation and clonogenicity of untransformed oral cells; cigarette smoke condensate (CSC) induces LDOC1 promoter hypermethylation via increased nuclear DNMT1 and DNMT3A, silencing LDOC1 expression.\",\n      \"method\": \"CSC treatment, quantitative methylation-specific PCR, DNMT1/DNMT3A nuclear accumulation assay, knockdown proliferation/clonogenicity assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic link between CSC, DNMTs, methylation, and functional loss-of-function phenotype, single lab\",\n      \"pmids\": [\"26317789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LDOC1 overexpression in papillary thyroid carcinoma TPC-1 cells suppresses NF-κB activation (reducing p65 nuclear translocation, IκBα degradation, c-Myc, and Bcl-xL), inhibits proliferation, induces apoptosis (increasing Bax), and restores responsiveness to TGF-β1 antiproliferative signaling.\",\n      \"method\": \"Lentiviral LDOC1 overexpression, NF-κB luciferase reporter assay, Western blot (p65, IκBα, c-Myc, Bax, Bcl-xL), flow cytometry, cell cycle analysis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing NF-κB as mechanistic node, single lab\",\n      \"pmids\": [\"26637328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LDOC1 interacts with GNL3L (a nucleolar GTPase) via protein-protein interaction; ectopic LDOC1 destabilizes endogenous GNL3L and down-modulates GNL3L-induced cell proliferation; GNL3L upregulates NF-κB-dependent transcriptional activity through p65, which is reversed by LDOC1 co-expression.\",\n      \"method\": \"Co-immunoprecipitation, ectopic expression/knockdown, NF-κB reporter assay, cell proliferation assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction shown with functional NF-κB and proliferation consequences, single lab\",\n      \"pmids\": [\"27764577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Stable knockdown of LDOC1 in ependymoma cell lines significantly increases transcription of RELA (v-rel/p65) and NF-κB target gene expression, including IL-6 secretion; demethylation of LDOC1 promoter by 5-AZA-DC restores LDOC1 expression and decreases IL-6 secretion.\",\n      \"method\": \"Stable shRNA knockdown, RT-PCR, ELISA (IL-6), demethylation treatment (5-AZA-DC), gene expression analysis\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined NF-κB/IL-6 pathway readout, epigenetic mechanism confirmed, single lab\",\n      \"pmids\": [\"28510691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LDOC1 forms protein complexes with phospho-JAK2 (pJAK2) and E3 ubiquitin ligase LNX1; LDOC1 targets pJAK2 for ubiquitin-dependent proteasomal degradation, thereby inhibiting STAT3 activation; LDOC1 deficiency attenuates LNX1-pJAK2 interaction, leading to ineffective pJAK2 ubiquitination and STAT3 activation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence confocal microscopy, ubiquitination assay, in vivo xenograft with LDOC1 knockdown measuring pJAK2/pSTAT3\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — complex mechanism (IP, co-localization, ubiquitination assay, in vivo) with multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"30634502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-4532 secreted by AML cells via exosomes targets LDOC1 mRNA in hematopoietic stem cells; LDOC1 suppression activates the JAK2/STAT3 signaling pathway, inhibiting normal hematopoiesis; ectopic LDOC1 expression or miR-4532 inhibition restores CFU and reduces DKK1 and JAK2/STAT3 phosphorylation.\",\n      \"method\": \"Luciferase reporter (miR-4532 targeting LDOC1 3'UTR), exosome co-culture, gain/loss-of-function, Western blot (pJAK2, pSTAT3), CFU assay\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation plus functional pathway readout, single lab\",\n      \"pmids\": [\"31842997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LDOC1 expression decreases Wnt5a levels in osteosarcoma cells and inhibits cell migration and invasion in vitro and lung metastasis in vivo.\",\n      \"method\": \"Lentiviral LDOC1 expression, Transwell migration/invasion assay, qRT-PCR array, xenograft micro-CT imaging\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo with defined Wnt5a pathway readout, single lab\",\n      \"pmids\": [\"28240050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LDOC1 expression downregulates the Wnt/β-catenin signaling pathway in colorectal cancer cells, reducing β-catenin nuclear localization, inhibiting proliferation and metastasis.\",\n      \"method\": \"Lentiviral overexpression, Western blot (β-catenin), immunofluorescence (β-catenin localization), Transwell assay, flow cytometry\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods linking LDOC1 to Wnt/β-catenin with subcellular readout, single lab\",\n      \"pmids\": [\"31002361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LDOC1 deficiency increases PI3K/Akt activation upon Candida albicans stimulation, leading to inhibitory phosphorylation of GSK-3β at Ser9 by activated Akt, resulting in enhanced IL-1β production; constitutively active GSK-3β(S9A) mutant or PI3K/Akt inhibitors reverse this effect.\",\n      \"method\": \"Loss/gain-of-function LDOC1 manipulation, Western blot (pAkt, pGSK-3βS9), PI3K/Akt inhibitor treatment, constitutively active GSK-3β mutant expression, IL-1β ELISA\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissected with inhibitors and dominant-active mutant, single lab\",\n      \"pmids\": [\"33120999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LINC01270 acts as a competing endogenous RNA (ceRNA) that sponges miR-326; miR-326 targets LDOC1 mRNA, so LINC01270 knockdown reduces LDOC1 expression, enhancing NF-κB activity and IL-6/IL-8/MCP-1 production; luciferase reporter assay confirmed LINC01270 overexpression suppresses NF-κB activation.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay, miRNA interactome analysis, synthetic RNA perturbation\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ceRNA axis validated by multiple orthogonal methods with NF-κB functional readout, single lab\",\n      \"pmids\": [\"39682774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LDOC1 interacts with histone H2B and H2Bub1 as well as with PSMA1 to promote their proteasomal degradation, limiting global H2Bub1 levels; LDOC1 knockdown causes loss of chromatin-bound H2Bub1 and enhanced chromatin compaction partially mediated through LDOC1-THAP12 interaction; LDOC1-H2Bub1 axis regulates metastasis-related genes (cytoskeletal remodeling, cell adhesion, EMT) and LDOC1 loss enhances TGF-β-induced epithelial-mesenchymal plasticity.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, ChIP-seq, ATAC-seq, MNase digestion assay, transcriptomic profiling, immunofluorescence, functional migration/adhesion assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (IP, PLA, ChIP-seq, ATAC-seq, MNase) in single rigorous study establishing epigenetic mechanism\",\n      \"pmids\": [\"41484780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In PFA1 ependymoma, H3K27me3 chromatin compaction at the LDOC1 locus silences LDOC1 expression; restoration of LDOC1 reduces NF-κB signaling, IL-6 secretion, and tumor cell proliferation; loss of LDOC1 is required for PFA tumor growth in vivo.\",\n      \"method\": \"ChIP (H3K27me3), lentiviral LDOC1 transduction, in vivo tumor competition assay, NF-κB signaling assay, IL-6 ELISA\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epigenetic mechanism and in vivo requirement established with multiple methods, single lab\",\n      \"pmids\": [\"39901723\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LDOC1 is a nuclear leucine-zipper protein that functions as a tumor suppressor through multiple mechanistic arms: it directly inhibits NF-κB signaling (suppressing p65/p50 and downstream cytokines including IL-6), interacts with GNL3L to reduce p65-driven proliferation, forms a complex with pJAK2 and E3 ligase LNX1 to promote ubiquitin-dependent proteasomal degradation of pJAK2 (thereby blocking JAK2/STAT3 activation), suppresses PI3K/Akt/GSK-3β-mediated IL-1β production, and regulates chromatin accessibility by controlling H2B monoubiquitination levels through interaction with H2B, H2Bub1, PSMA1, and THAP12; additionally, LDOC1 is negatively regulated by WAVE3, which sequesters it from the nucleus to the cytoplasm, and by miRNAs (miR-4532, miR-326, miR-330-5p) delivered via exosomes or sponged by lncRNAs, while in the placenta LDOC1 regulates trophoblast giant cell differentiation and progesterone production.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LDOC1 is a nuclear leucine-zipper protein that functions as a tumor suppressor by restraining NF-κB, JAK2/STAT3, PI3K/Akt, and Wnt/β-catenin signaling pathways and by regulating chromatin organization through control of histone H2B monoubiquitination. LDOC1 directly inhibits NF-κB transcriptional activity by suppressing p65/p50 expression and nuclear translocation, thereby reducing downstream cytokine production including IL-6 [PMID:12712434, PMID:28510691, PMID:26637328]; it also forms a ternary complex with phospho-JAK2 and the E3 ubiquitin ligase LNX1 to promote ubiquitin-dependent proteasomal degradation of pJAK2, blocking STAT3 activation [PMID:30634502]. LDOC1 interacts with histone H2B, H2Bub1, PSMA1, and THAP12 to limit global H2Bub1 levels and regulate chromatin accessibility at metastasis-related gene loci, and its loss enhances TGF-β-induced epithelial–mesenchymal plasticity [PMID:41484780]. In the placenta, LDOC1 knockout causes aberrant trophoblast giant cell differentiation and progesterone overproduction leading to delayed parturition [PMID:25468940].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The initial characterization of LDOC1 established it as a nuclear protein with a leucine-zipper-like motif and SH3-binding domain, providing the structural basis for subsequent interaction studies.\",\n      \"evidence\": \"EGFP fusion imaging and Northern blot in human cell lines\",\n      \"pmids\": [\"10403563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No interaction partners or functional consequence identified\", \"Localization confirmed only by overexpressed fusion protein\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"LDOC1 was shown to suppress NF-κB transcriptional activity and sensitize cancer cells to TNF-α/PMA-induced apoptosis, establishing NF-κB inhibition as its core tumor-suppressive mechanism.\",\n      \"evidence\": \"NF-κB luciferase reporter, stable transfection, and viability assays in BxPC-3 pancreatic cancer cells\",\n      \"pmids\": [\"12712434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of NF-κB inhibition not defined\", \"No loss-of-function validation\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Two studies revealed that LDOC1 interacts with MZF-1 to potentiate apoptosis through mitochondrial and caspase pathways, and that WAVE3 sequesters LDOC1 from the nucleus to the cytoplasm to antagonize its pro-apoptotic function, establishing regulation of LDOC1 by subcellular relocalization.\",\n      \"evidence\": \"Co-immunoprecipitation, pulldown with domain mapping, fluorescence microscopy, annexin V/JC-1 flow cytometry\",\n      \"pmids\": [\"15670815\", \"16272576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of WAVE3-LDOC1 axis in tumors not demonstrated\", \"p53 stabilization mechanism not molecularly defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Restoration of LDOC1 (with BEX1) in oral squamous cell carcinoma cells confirmed NF-κB suppression through reduced p50/p65 protein and demonstrated growth inhibition in vivo, extending the NF-κB axis to a second cancer type.\",\n      \"evidence\": \"Ectopic expression, Western blot for p50/p65, in vitro and xenograft growth assays\",\n      \"pmids\": [\"23362108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Individual contribution of LDOC1 versus BEX1 not fully separated\", \"Mechanism of p50/p65 protein reduction unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Knockout of Ldoc1 (Sirh7) in mice revealed its non-oncological role in trophoblast giant cell differentiation and placental endocrine control, demonstrating that LDOC1 restrains progesterone and PL1 production to ensure timely parturition.\",\n      \"evidence\": \"Ldoc1 knockout mouse, placental histology, P4 and PL1 hormone measurement\",\n      \"pmids\": [\"25468940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets of LDOC1 in trophoblasts not identified\", \"Whether NF-κB or JAK2/STAT3 pathways are involved in placental phenotype is unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Cigarette smoke condensate was shown to silence LDOC1 via DNMT1/DNMT3A-mediated promoter hypermethylation, and LDOC1 loss promoted proliferation/clonogenicity, linking an environmental carcinogen to epigenetic LDOC1 inactivation.\",\n      \"evidence\": \"CSC treatment, methylation-specific PCR, DNMT nuclear accumulation, knockdown proliferation assays in oral keratinocytes\",\n      \"pmids\": [\"26317789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNMT recruitment to LDOC1 promoter not shown by ChIP\", \"Whether CSC-induced methylation is reversible in vivo is untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of GNL3L as a direct LDOC1 interactor established a mechanism by which LDOC1 destabilizes GNL3L and reverses GNL3L-driven NF-κB/p65 activation and proliferation.\",\n      \"evidence\": \"Co-immunoprecipitation, ectopic expression/knockdown, NF-κB reporter, proliferation assay\",\n      \"pmids\": [\"27764577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of GNL3L destabilization (proteasomal? transcriptional?) not defined\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Stable LDOC1 knockdown in ependymoma cells increased RELA transcription and IL-6 secretion, and demethylation restored LDOC1 expression, demonstrating that epigenetic LDOC1 silencing drives NF-κB-dependent cytokine production in brain tumors.\",\n      \"evidence\": \"Stable shRNA knockdown, ELISA for IL-6, 5-AZA-DC demethylation in ependymoma cell lines\",\n      \"pmids\": [\"28510691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LDOC1 directly regulates RELA transcription or acts indirectly is unknown\", \"Single cell line system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"LDOC1 was shown to bridge pJAK2 to the E3 ligase LNX1, promoting ubiquitin-dependent pJAK2 degradation and STAT3 inactivation, revealing an adaptor function in targeted protein turnover and a second major signaling axis suppressed by LDOC1.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, confocal microscopy, in vivo xenograft with LDOC1 knockdown\",\n      \"pmids\": [\"30634502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ternary complex formation unknown\", \"Whether LDOC1 similarly directs degradation of other substrates is unexplored\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Exosomal miR-4532 from AML cells was identified as a negative regulator of LDOC1 in hematopoietic stem cells, linking LDOC1 suppression to JAK2/STAT3-mediated disruption of normal hematopoiesis in the leukemic niche.\",\n      \"evidence\": \"Luciferase reporter for miR-4532–LDOC1 3′UTR, exosome co-culture, CFU assay, Western blot for pJAK2/pSTAT3\",\n      \"pmids\": [\"31842997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo validation of exosomal miR-4532 niche effect not performed\", \"Whether LDOC1 is the sole relevant target of miR-4532 is unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"LDOC1 was found to suppress Wnt/β-catenin signaling, reducing β-catenin nuclear localization and Wnt5a levels, broadening LDOC1's tumor-suppressive reach to a third major oncogenic pathway.\",\n      \"evidence\": \"Lentiviral overexpression, Western blot and immunofluorescence for β-catenin, Transwell assays, xenograft imaging in osteosarcoma and colorectal cancer cells\",\n      \"pmids\": [\"28240050\", \"31002361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism linking LDOC1 to Wnt pathway components not identified\", \"Relationship between Wnt suppression and NF-κB suppression unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"LDOC1 deficiency was shown to enhance PI3K/Akt activation and inhibitory GSK-3β phosphorylation, leading to increased IL-1β production, establishing a PI3K/Akt/GSK-3β axis as another pathway restrained by LDOC1.\",\n      \"evidence\": \"Loss/gain-of-function, PI3K/Akt inhibitors, constitutively active GSK-3β(S9A) mutant, IL-1β ELISA upon Candida stimulation\",\n      \"pmids\": [\"33120999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct target of LDOC1 in PI3K/Akt pathway not identified\", \"Relevance to cancer versus innate immunity not delineated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The lncRNA LINC01270 was identified as a ceRNA sponging miR-326 to protect LDOC1 mRNA, establishing a second miRNA-based regulatory axis controlling LDOC1-dependent NF-κB suppression.\",\n      \"evidence\": \"siRNA knockdown, luciferase reporter, miRNA interactome analysis\",\n      \"pmids\": [\"39682774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo ceRNA axis validation lacking\", \"Relative importance of miR-326 versus miR-4532 in LDOC1 regulation unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"LDOC1 was revealed to regulate chromatin organization by interacting with H2B, H2Bub1, PSMA1, and THAP12 to control H2Bub1 levels, chromatin accessibility, and expression of metastasis-related genes, representing a fundamental epigenetic mechanism distinct from its signaling pathway functions.\",\n      \"evidence\": \"Co-immunoprecipitation, proximity ligation assay, ChIP-seq, ATAC-seq, MNase digestion, transcriptomics, migration/adhesion assays\",\n      \"pmids\": [\"41484780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H2Bub1 regulation underlies LDOC1's effects on NF-κB, JAK2/STAT3, and Wnt pathways is untested\", \"Structural basis of LDOC1-H2Bub1 interaction unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"H3K27me3-mediated silencing at the LDOC1 locus was shown to be required for PFA ependymoma growth, and LDOC1 restoration suppressed NF-κB/IL-6 and tumor growth in vivo, confirming LDOC1 as a bona fide tumor suppressor in this brain tumor.\",\n      \"evidence\": \"ChIP for H3K27me3, lentiviral LDOC1 restoration, in vivo tumor competition assay, IL-6 ELISA\",\n      \"pmids\": [\"39901723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether H3K27me3 silencing is driven by EZH2 or other methyltransferases at LDOC1 not tested\", \"Therapeutic strategies to restore LDOC1 in PFA not explored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether LDOC1's epigenetic function (H2Bub1 regulation) mechanistically underlies its suppression of NF-κB, JAK2/STAT3, PI3K/Akt, and Wnt/β-catenin signaling, or whether these represent independent parallel functions; no structural model of LDOC1 or its complexes exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of LDOC1 or any of its complexes determined\", \"Hierarchy among multiple suppressed pathways unresolved\", \"Physiological relevance of LDOC1 in non-cancer adult tissues beyond placenta unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 7, 8, 10, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 4, 7, 8, 9, 15, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 10, 11, 13, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 14, 15]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"WAVE3\",\n      \"MZF1\",\n      \"GNL3L\",\n      \"LNX1\",\n      \"JAK2\",\n      \"PSMA1\",\n      \"THAP12\",\n      \"H2BC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}