{"gene":"FOXQ1","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2001,"finding":"FOXQ1 (HFH-1) is mutant in satin (sa) mice, which display structurally abnormal medulla cells and defects in hair shaft differentiation. A missense mutation in the conserved winged helix DNA-binding domain causes the same phenotype as an intragenic deletion, establishing FOXQ1 as required for hair medulla differentiation.","method":"Genetic mapping, identification of intragenic deletion and ENU-induced missense mutation in DNA-binding domain, phenotypic characterization of homozygous mutants","journal":"Genesis","confidence":"High","confidence_rationale":"Tier 1 / Strong — two independent alleles (deletion and missense in DNA-binding domain) produce identical phenotype, establishing causality; replicated across alleles","pmids":["11309849"],"is_preprint":false},{"year":2000,"finding":"HFH-1 (FOXQ1) represses transcription of smooth muscle-specific promoters (telokin, SM22α) by binding to a forkhead consensus site in an AT-rich region of the telokin promoter. The DNA-binding domain alone is sufficient for repression, and HFH-1 does not disrupt serum response factor binding to adjacent CArG boxes, indicating it blocks other positive-acting factors.","method":"Reporter gene (promoter-luciferase) assays in A10 vascular smooth muscle cells, overexpression of HFH-1 and DNA-binding domain alone, gel-shift/footprint to map binding site","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro transcription assay with domain-deletion mapping, multiple promoter targets tested, single lab","pmids":["10896677"],"is_preprint":false},{"year":2002,"finding":"The DNA-binding domain of HFH-1 (FOXQ1) adopts a winged-helix fold that forms DNA complexes with different local conformations than the closely related Genesis protein when contacting the same DNA sequence, as determined by heteronuclear NMR.","method":"Heteronuclear NMR structure determination of HFH-1 DNA-binding domain in free and DNA-bound states; structural comparison with Genesis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional comparison; single lab but direct structural method","pmids":["11876636"],"is_preprint":false},{"year":2001,"finding":"The human FOXQ1 gene encodes a 403-amino acid protein with a conserved HNF-3/forkhead DNA-binding domain (100% identity with mouse and rat) and two putative transcriptional activation domains. The gene is expressed predominantly in stomach, trachea, bladder, and salivary gland.","method":"Isolation and sequencing of human genomic and cDNA clones; sequence alignment; tissue expression by Northern/RT-PCR","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cDNA characterization and domain annotation; single lab but foundational molecular characterization","pmids":["11747606"],"is_preprint":false},{"year":2006,"finding":"FOXQ1 is a direct downstream transcriptional target of HOXC13 during hair follicle medulla differentiation. HOXC13 binds the Foxq1 promoter and activates its expression, as shown by DNA binding studies, co-transfection reporter assays, and ChIP. Expression of additional medulla-specific genes depends on functional Foxq1, placing FOXQ1 downstream of HOXC13 in a hair differentiation pathway.","method":"ChIP assay, co-transfection/reporter assay, gene array in Hoxc13-transgenic mice, validation in satin (Foxq1-mutant) mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP plus reporter assay plus genetic epistasis (satin mouse), multiple orthogonal methods in one study","pmids":["16835220"],"is_preprint":false},{"year":2008,"finding":"FOXQ1 is required for gastric acid secretion in mice. Foxq1-deficient mice lack gastric acid secretion in response to secretagogue stimuli despite normal parietal cell development; ultrastructural analysis suggests impaired fusion of cytoplasmic tubulovesicles with the apical membrane of secretory canaliculi.","method":"Foxq1 knockout mouse model, gastric acid secretion assays with secretagogues, transmission electron microscopy, parietal cell morphology analysis","journal":"Cytogenetic and genome research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — loss-of-function (knockout) with specific functional readout (acid secretion) and ultrastructural mechanism; single lab","pmids":["18544931"],"is_preprint":false},{"year":2010,"finding":"FOXQ1 transcriptionally activates p21(CIP1/WAF1) by binding to its promoter, as shown by reporter assay and ChIP. FOXQ1 overexpression also upregulates VEGFA, WNT3A, RSPO2, and BCL11A, mediating angiogenic and antiapoptotic effects in vivo.","method":"siRNA knockdown microarray analysis, luciferase reporter assay, chromatin immunoprecipitation (ChIP), stable overexpression xenograft model, CD31 and TUNEL staining","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP plus reporter assay identifying direct transcriptional target, supported by in vivo xenograft data; single lab","pmids":["20145154"],"is_preprint":false},{"year":2011,"finding":"FOXQ1 promotes EMT and breast cancer metastasis by directly repressing E-cadherin (CDH1) expression through binding to the E-box in its promoter region. FOXQ1 expression is induced by TGF-β1, and FOXQ1 knockdown blocks TGF-β1-induced EMT.","method":"Ectopic expression and shRNA knockdown, in vitro migration/invasion assays, in vivo lung metastasis model, ChIP and promoter binding assay for E-cadherin E-box","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP demonstrating direct promoter binding, genetic loss-of-function, and in vivo metastasis model; replicated in parallel by a second group (PMID 21346143)","pmids":["21285253","21346143"],"is_preprint":false},{"year":2011,"finding":"FOXQ1 promotes EMT in breast cancer cells; RNAi suppression of FOXQ1 reverses EMT, and enforced FOXQ1 expression induces EMT in differentiated human mammary epithelial cells associated with transcriptional inactivation of E-cadherin (CDH1).","method":"RNAi knockdown, ectopic expression, 3D Matrigel culture, CDH1 promoter reporter assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — independent replication of FOXQ1-CDH1 repression with multiple orthogonal methods across two labs (PMID 21285253 and 21346143)","pmids":["21346143"],"is_preprint":false},{"year":2011,"finding":"Repression of FoxQ1 in mammary epithelial cells increases E-cadherin expression, promotes cell-cell contacts, rearranges the actin cytoskeleton, slows G1-phase cell cycle progression, and enhances migration of coherent epithelial sheets. FoxQ1 was identified as a downstream mediator of TGF-β1-induced gene expression changes including Ets-1, Zeb1, and Zeb2.","method":"FoxQ1 knockdown by RNAi, cell morphology analysis, gene expression profiling, cell cycle analysis by flow cytometry, migration assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes and gene expression profiling; single lab","pmids":["20717954"],"is_preprint":false},{"year":2013,"finding":"FOXQ1 directly binds the TWIST1 promoter and transcriptionally activates TWIST1 expression, thereby modulating TWIST1-dependent metastatic phenotypes in colorectal cancer cells. Enhanced FOXQ1 expression increased migration, invasion, and distant metastasis in a chicken chorioallantoic membrane model.","method":"ChIP assay, luciferase reporter assay, forced expression and RNA silencing, in vivo chorioallantoic membrane metastasis assay","journal":"Molecular cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP plus reporter assay demonstrating direct promoter binding of TWIST1 by FOXQ1; supported by in vivo metastasis model","pmids":["23723077"],"is_preprint":false},{"year":2013,"finding":"FoxQ1 directly binds the NRXN3 promoter and represses its transcriptional activity, promoting glioma cell proliferation and migration. Knockdown of FoxQ1 reduces these behaviors, while NRXN3 expression is negatively correlated with FoxQ1 in glioma tissues.","method":"ChIP assay, luciferase reporter assay, stable FoxQ1 knockdown and overexpression cell lines, MTT proliferation assay, transwell migration assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP and reporter assay with functional validation; single lab","pmids":["23383267"],"is_preprint":false},{"year":2013,"finding":"FOXQ1 is a direct transcriptional target of canonical Wnt signaling. FOXQ1 promoter contains Wnt-responsive elements, and Wnt pathway activation induces FOXQ1 expression as demonstrated by ChIP and luciferase reporter assays.","method":"ChIP, luciferase reporter assay, qRT-PCR and western blot in Wnt-stimulated CRC cell lines and laser microdissected human biopsies","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP and reporter assays directly demonstrating Wnt-responsive element occupancy; single lab but multiple methods","pmids":["23555880"],"is_preprint":false},{"year":2014,"finding":"FOXQ1 directly binds the Sox12 promoter and transactivates Sox12 expression in hepatocellular carcinoma. Sox12 in turn activates Twist1 and FGFBP1 transcription to promote HCC invasion and metastasis, placing FOXQ1 upstream of the Sox12-Twist1/FGFBP1 axis.","method":"Serial deletion, site-directed mutagenesis, and ChIP assays on Sox12 promoter; siRNA knockdown and rescue experiments; in vivo metastasis models","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP plus site-directed mutagenesis of promoter plus functional rescue in vivo; single lab","pmids":["25704764"],"is_preprint":false},{"year":2014,"finding":"Foxq1 promotes breast cancer stemness traits and chemoresistance by transcriptionally activating PDGFRα and PDGFRβ directly or indirectly through the Foxq1/Twist1 axis. Knockdown of both PDGFRα and β reverses Foxq1-promoted oncogenesis more effectively than either alone; PDGFRβ is the more potent mediator of Foxq1-promoted stemness.","method":"Expression profiling, siRNA knockdown, pharmacological PDGFR inhibition, in vitro stemness assays, in vivo xenograft model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological epistasis, in vivo validation; single lab","pmids":["25502837"],"is_preprint":false},{"year":2014,"finding":"FOXQ1 directly binds the TGF-β1 promoter (E-cadherin and N-cadherin promoter regions confirmed by ChIP) and activates TGF-β1 expression, and TGF-β1 in turn upregulates FOXQ1, forming a positive feedback loop that drives EMT.","method":"ChIP assay, shRNA knockdown, wound healing and invasion assays, RT-PCR","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP assay supporting direct binding; single lab, single ChIP method for TGF-β1 target claim","pmids":["25287361"],"is_preprint":false},{"year":2015,"finding":"FOXQ1 silencing in colorectal cancer cells prevents nuclear translocation of β-catenin, thereby reducing Wnt signaling activity. Additionally, TGF-β1 induces FOXQ1 expression and promotes cancer cell migration/invasion via FOXQ1, placing FOXQ1 as a mediator of crosstalk between TGF-β and Wnt signaling pathways.","method":"siRNA knockdown, β-catenin nuclear fractionation and immunofluorescence, in vitro invasion/migration assays, TGF-β1 stimulation","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear fractionation and functional assays; single lab, no direct binding assay for β-catenin","pmids":["25955104"],"is_preprint":false},{"year":2015,"finding":"FOXQ1 transcriptionally represses CDH1 (E-cadherin) in esophageal cancer by binding to its promoter as a transcriptional repressor, promoting cell proliferation and metastasis. CDH1 silencing rescues migratory ability lost by FOXQ1 knockdown.","method":"Reporter gene assay, RT-PCR, western blot, overexpression and knockdown, migration chamber assay, rescue experiment","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with rescue experiment; single lab","pmids":["26349968"],"is_preprint":false},{"year":2016,"finding":"FOXQ1 directly binds the SIRT1 promoter and transcriptionally upregulates SIRT1, which in turn inhibits NF-κB-driven expression of inflammatory cytokines IL-6 and IL-8. This FOXQ1-SIRT1 axis suppresses replicative senescence in human fibroblasts.","method":"ChIP assay demonstrating FOXQ1 binding to SIRT1 promoter, FOXQ1 overexpression and knockdown, cytokine measurement, senescence assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP plus functional phenotype with defined downstream pathway (SIRT1-NF-κB); single lab, multiple methods","pmids":["28726780"],"is_preprint":false},{"year":2016,"finding":"Hepatic FOXQ1 regulates gluconeogenesis by interacting with FOXO1 and blocking its binding to insulin response elements in gluconeogenic gene promoters. FOXQ1 rescue in diabetic mice decreases blood glucose; FOXQ1 deficiency increases blood glucose and impairs glucose tolerance.","method":"Primary hepatocyte overexpression/deficiency, in vivo FOXQ1 hepatic rescue in db/db and HFD-obese mice, glucose tolerance tests, co-immunoprecipitation of FOXQ1-FOXO1 interaction, promoter binding assays","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 1 / Moderate — Co-IP identifying FOXQ1-FOXO1 interaction, in vivo loss- and gain-of-function with defined metabolic phenotype; single lab","pmids":["27421728"],"is_preprint":false},{"year":2016,"finding":"FOXQ1 promotes colorectal cancer cell migration and invasion through activation of PI3K/AKT signaling. FOXQ1 knockdown reduces phosphorylated FAK, PI3K, and AKT levels as well as MMP-2/9 expression.","method":"siRNA knockdown, western blot for signaling components, migration/invasion assays, in vivo xenograft","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — western blot for pathway components without direct binding/epistasis experiment; single lab, single method","pmids":["28559972"],"is_preprint":false},{"year":2016,"finding":"FOXQ1 regulates prostate cancer cell proliferation and apoptosis by controlling BCL11A and MDM2 expression. Overexpression of BCL11A reverses the pro-apoptotic effects of FOXQ1 inhibition and restores MDM2 expression, placing BCL11A downstream of FOXQ1.","method":"siRNA knockdown, BCL11A overexpression rescue assay, flow cytometry apoptosis, western blot","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment placing BCL11A in FOXQ1 pathway; single lab","pmids":["27573292"],"is_preprint":false},{"year":2017,"finding":"FOXQ1 directly binds the NDRG1 promoter and transactivates NDRG1 expression in HCC, which activates pSTAT6/CCL26 signaling to recruit hepatic stellate cells and create a positive feedback loop with cancer-associated fibroblasts enhancing tumor initiation.","method":"ChIP assay, luciferase reporter assay, Co-culture models, siRNA knockdown, in vivo HCC initiation assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay with mechanistic co-culture model; single lab","pmids":["29248714"],"is_preprint":false},{"year":2017,"finding":"FOXQ1 functions as a melanoma suppressor rather than oncogene, suppressing EMT, invasion, and metastasis in melanocyte lineage cells. This lineage-specific reversal depends on FOXQ1's ability to repress (in melanoma) rather than activate (in carcinomas) N-cadherin (CDH2) transcription. The switch is determined by the nuclear β-catenin/TLE ratio: high in carcinomas drives CDH2 activation; low in melanoma drives repression. FOXQ1 interacts with nuclear β-catenin and TLE proteins.","method":"Reciprocal Co-IP of FOXQ1 with β-catenin and TLE proteins, loss- and gain-of-function in melanoma and carcinoma cells, in vivo xenograft/metastasis models, manipulation of β-catenin and TLE levels to switch CDH2 regulation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — Co-IP identifying binding partners, mechanistic rescue by altering β-catenin/TLE ratio, in vivo validation; single lab, multiple orthogonal methods","pmids":["28930679"],"is_preprint":false},{"year":2017,"finding":"FOXQ1 promotes NKTCL cell proliferation and blocks apoptosis via the Sonic Hedgehog (Shh) signaling pathway; FOXQ1 knockdown downregulates Shh pathway proteins, blocks cells in G0/G1, and increases apoptosis with elevated Bax/Caspase-3 and reduced Bcl-2. Exogenous Shh reverses the effects of FOXQ1 knockdown.","method":"shRNA knockdown, Shh pathway inhibitor (Cyclopamine) and recombinant Shh rescue, CCK-8, BrdU incorporation, flow cytometry, western blot","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic rescue epistasis; single lab","pmids":["29132010"],"is_preprint":false},{"year":2017,"finding":"IL-4 induces FoxQ1 expression in human monocytes and macrophages. FoxQ1 overexpression in RAW264.7 monocytic cells facilitates their migration towards MCP-1 and is associated with decreased expression of migration-regulating genes claudin-11 and plexin C1, and increases TNFα secretion after LPS challenge.","method":"IL-4 stimulation of primary monocytes and macrophages, FoxQ1 overexpression in RAW cells, migration assay, RT-PCR for target genes, TNFα ELISA","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined cellular phenotype and downstream gene changes; single lab","pmids":["29203829"],"is_preprint":false},{"year":2018,"finding":"FOXQ1 directly activates MITF gene transcription to induce differentiation in normal and transformed melanocytic cells. FOXQ1-mediated pigmentation depends on activation of the cAMP/CREB1 pathway, and FOXQ1 mediates BRAFV600E-dependent regulation of MITF levels.","method":"ChIP and promoter reporter assays for MITF, cAMP/CREB1 pathway activation experiments, BRAFV600E expression models, gain- and loss-of-function in melanocytic cells and in vivo mouse pigmentation models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP plus reporter assay demonstrating direct MITF promoter activation, in vivo mouse model; single lab","pmids":["29463842"],"is_preprint":false},{"year":2018,"finding":"EWS-FLI1 cooperates with Foxq1 in mouse Ewing sarcoma through a direct protein-protein interaction (EWS portion of EWS-FLI1 binds Foxq1). Foxq1 Fox-motif binding sites are enriched within EWS-FLI1 ChIP-seq peaks. Trib1 and Nrg1 are co-regulated target genes of EWS-FLI1/Foxq1 important for cell proliferation and survival.","method":"ChIP-seq for EWS-FLI1 binding, Co-immunoprecipitation of Foxq1 with EWS-FLI1, motif analysis, target gene validation","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP-seq; single lab","pmids":["29945296"],"is_preprint":false},{"year":2019,"finding":"FOXF2 and FOXQ1 engage in mutual transcriptional repression in basal-like breast cancer. FOXF2 recruits nuclear receptor corepressor 1 (NCoR1) and HDAC3 to the FOXQ1 promoter to suppress FOXQ1 transcription, whereas FOXQ1 does not use this mechanism to repress FOXF2.","method":"ChIP assay demonstrating NCoR1/HDAC3 recruitment to FOXQ1 promoter by FOXF2, luciferase reporter assays, ectopic expression and knockdown experiments","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP identifying specific corepressor recruitment mechanism; reporter assays with gain/loss of function; single lab","pmids":["30807702"],"is_preprint":false},{"year":2020,"finding":"HuR (ELAVL1) RNA-binding protein directly binds FOXQ1 mRNA and stabilizes it. The HuR inhibitor KH-3 disrupts the HuR-FOXQ1 mRNA interaction, leading to inhibition of breast cancer invasion and metastasis.","method":"RNA immunoprecipitation (RIP) identifying HuR-FOXQ1 mRNA interaction, HuR inhibitor KH-3 treatment, in vitro invasion assays, in vivo lung metastasis model","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — RIP confirming direct RNA-protein interaction plus pharmacological disruption with functional readout; single lab","pmids":["32332873"],"is_preprint":false},{"year":2020,"finding":"FOXQ1 promotes osteogenic differentiation of bone mesenchymal stem cells (BMSCs) by promoting nuclear translocation of β-catenin and enhancing Wnt/β-catenin signaling. FOXQ1 physically interacts with Annexin A2 (ANXA2), and ANXA2 depletion reverses the FOXQ1-promoted Wnt/β-catenin activation.","method":"Lentiviral overexpression/knockdown of Foxq1, TOPFlash/FOPFlash reporter, immunofluorescence for β-catenin, Co-IP mass spectrometry identifying ANXA2 as FOXQ1-binding partner, ANXA2 siRNA rescue","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identifying binding partner with functional rescue; single lab","pmids":["32943107"],"is_preprint":false},{"year":2021,"finding":"FOXQ1 directly regulates transcription of electron transport chain Complex I subunits NDUFS1 and NDUFV1 by binding to their promoters (ChIP). FOXQ1 overexpression increases Complex I assembly and activity, oxygen consumption, and intracellular pyruvate, lactate, and ATP levels in breast cancer cells.","method":"ChIP assay for FOXQ1 at NDUFS1 and NDUFV1 promoters, RNA-seq after FOXQ1 overexpression, Complex I activity and assembly assays, Seahorse oxygen consumption measurement","journal":"Molecular carcinogenesis","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP establishing direct promoter binding of metabolic target genes plus functional metabolic assays; single lab","pmids":["34939230"],"is_preprint":false},{"year":2021,"finding":"FOXQ1 directly binds the LDHA gene promoter in mouse Sertoli cells and transactivates Ldha expression, thereby regulating lactate production essential for germ cell survival. Foxq1-knockout males are subfertile with oligoasthenozoospermia due to lactate deficiency; LDHA overexpression rescues lactate production in Foxq1-deficient Sertoli cells.","method":"CRISPR-Cas9 Foxq1 knockout mice, ChIP assay for FOXQ1 at Ldha promoter, lentiviral LDHA overexpression rescue, lactate measurement, fertility phenotyping","journal":"Histochemistry and cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP plus genetic knockout with defined metabolic phenotype plus rescue experiment; single lab","pmids":["34091745"],"is_preprint":false},{"year":2021,"finding":"FOXQ1 directly binds the EGFR promoter and transcriptionally activates EGFR expression in NPC cells, promoting vasculogenic mimicry (VM) formation and metastasis via the EGFR signaling pathway. EGFR inhibitors (Nimotuzumab or Erlotinib) block Foxq1-induced VM.","method":"Luciferase reporter gene assay, ChIP assay for Foxq1 at EGFR promoter, in vitro VM formation, in vivo metastasis model, EGFR inhibitor treatment","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP plus reporter assay establishing direct EGFR promoter binding; pharmacological epistasis; single lab","pmids":["33875643"],"is_preprint":false},{"year":2022,"finding":"FOXQ1 initiates EMT by recruiting the MLL/KMT2 histone methyltransferase complex as a transcriptional coactivator. The Forkhead box domain of FOXQ1 directly binds the MLL core complex subunit RbBP5 without disrupting FOXQ1 DNA binding. FOXQ1 promoter recognition precedes MLL complex assembly and H3K4me3 deposition at EMT gene promoters. Disruption of the FOXQ1-RbBP5 interaction or pharmacologic targeting of KMT2/MLL inhibits EMT and in vivo tumor progression.","method":"Co-IP of FOXQ1 with MLL complex subunits including RbBP5, domain-mapping mutagenesis of FOXQ1-RbBP5 interaction, ChIP-seq for H3K4me3 at EMT gene promoters, pharmacologic KMT2 inhibition, in vivo tumor progression assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP with mutagenesis, ChIP-seq, pharmacological epistasis, and in vivo validation; multiple orthogonal methods in single rigorous study","pmids":["36319643"],"is_preprint":false},{"year":2022,"finding":"FOXQ1 directly binds the SIRT1 promoter and transcriptionally activates SIRT1; SIRT1 in turn enhances β-catenin expression and nuclear translocation, augmenting Wnt signaling, stemness, and radio-resistance of CRC cells.","method":"Luciferase reporter assay, Co-IP, ChIP assay for FOXQ1 at SIRT1 promoter, FOXQ1/SIRT1 knockdown and overexpression, xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP and Co-IP plus reporter assay; single lab","pmids":["35183223"],"is_preprint":false},{"year":2022,"finding":"FOXQ1 is a differential activator of Wnt target gene expression. Upon Wnt pathway activation, FOXQ1 synergizes with the β-catenin nuclear complex to boost major Wnt targets; in parallel, FOXQ1 independently controls other Wnt target genes in a β-catenin-independent manner. FOXQ1 occupies Wnt-responsive elements in β-catenin target gene promoters and recruits a similar set of co-factors as TCF7L1.","method":"RNA-seq in CRC cell lines, ChIP for FOXQ1 at Wnt-responsive elements, comparison of co-factor recruitment with TCF7L1, FOXQ1 knockdown in Wnt-stimulated cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP plus RNA-seq plus co-factor comparison; multiple orthogonal methods; single lab","pmids":["36124643"],"is_preprint":false},{"year":2022,"finding":"FOXQ1 and SNAI1 act as independent EMT transcription factors sharing a common downstream target DDR2 (the most upregulated receptor tyrosine kinase). DDR2 is a shared effector mediating cell motility without significantly affecting EMT marker expression or stem cell population. DDR2 knockdown in FOXQ1-driven EMT models alters the global metabolic profile including glutamine-glutamate and aspartate recycling.","method":"Ectopic expression of FOXQ1 and SNAI1 in HMLE cells, transcriptomic analysis, DDR2 knockdown and overexpression, motility assays, metabolomics","journal":"Cancer research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomic identification plus genetic loss-of-function epistasis and metabolomics; single lab","pmids":["36713812"],"is_preprint":false},{"year":2022,"finding":"STUB1 directs FOXQ1-mediated transactivation of Ldha in mouse Sertoli cells via K63-linked non-proteolytic polyubiquitination of FOXQ1, facilitating lactate production in FSH-stimulated Sertoli cells. Conditional Stub1 knockout in Sertoli cells impairs fertility due to lactate deficiency.","method":"Sertoli cell-specific Stub1 conditional knockout (Amh-Cre), ChIP assay, in vivo ubiquitination assay, luciferase reporter assay, lentiviral LDHA overexpression rescue","journal":"Cell and tissue research","confidence":"High","confidence_rationale":"Tier 1 / Strong — conditional KO with defined fertility phenotype, ChIP, ubiquitination assay, and rescue; multiple orthogonal methods","pmids":["36575252"],"is_preprint":false},{"year":2023,"finding":"FOXQ1 directly binds the circ_0000643 host gene promoter (ChIP assay) to increase circ_0000643 levels. circ_0000643 then sponges miR-153, which relieves repression of SLC7A11, reducing ferroptosis in breast cancer cells.","method":"ChIP assay for FOXQ1 at circ_0000643 host gene promoter, luciferase reporter assay, RIP assay for circ_0000643-miR-153 interaction, ferroptosis assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP establishing direct promoter binding; RIP confirming ceRNA interaction; single lab","pmids":["37591453"],"is_preprint":false},{"year":2023,"finding":"FOXQ1 promotes LDHA transcription in pancreatic cancer cells to modulate aerobic glycolysis, thereby enhancing cell proliferation, tumor stemness, invasion, and metastasis. FOXQ1 silencing reduces LDHA expression and glycolysis.","method":"FOXQ1 overexpression and knockdown, ChIP assay for FOXQ1 at LDHA promoter, glycolysis measurement, in vivo xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP identifying direct LDHA promoter binding; single lab","pmids":["37875474"],"is_preprint":false},{"year":2023,"finding":"KSHV immediate early protein ORF45 induces FOXQ1 expression in oral epithelial cells via the ORF45-RSK (ERK-p90RSK) signaling pathway. RTA also induces FOXQ1. FOXQ1 depletion reduces KSHV lytic protein accumulation and viral DNA, identifying FOXQ1 as a lytic cycle-sustaining host factor. FOXQ1 induction is associated with accumulation of activating histone acetylation marks at the FOXQ1 promoter.","method":"Transcriptome analysis of KSHV-infected HGEP cells, FOXQ1 knockdown in TIGK cells, screen of KSHV lytic proteins by ectopic expression, ORF45 RSK-activation mutant, ChIP for histone acetylation at FOXQ1 promoter","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function plus viral protein screen identifying upstream inducer mechanism; single lab","pmids":["36815831"],"is_preprint":false},{"year":2023,"finding":"FOXQ1 transcriptionally activates CREB5, which suppresses NF-κB nuclear translocation of p65 to protect against sepsis-induced acute kidney injury. USP10 deubiquitinates FOXQ1, reducing its ubiquitination and promoting protein stability, and USP10 overexpression alleviates LPS-induced cell injury through FOXQ1.","method":"CLP mouse model, LPS-induced HK-2 cell model, luciferase reporter for CREB5, Co-IP for USP10-FOXQ1 interaction, in vivo ubiquitination assay, phosphorylation level assessment of p65","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay and reporter assay; in vivo and in vitro models; single lab","pmids":["38960057"],"is_preprint":false},{"year":2023,"finding":"NAC1 interacts with BCL6 via NAC1's C-terminal BEN domain, and the NAC1-BCL6 complex binds the FOXQ1 promoter to activate FOXQ1 transcription. NAC1 also attenuates BCL6 auto-downregulation in ovarian cancer.","method":"Co-IP of NAC1 and BCL6, ChIP of NAC1-BCL6 complex at FOXQ1 promoter, luciferase reporter assay, Cistrome database analysis","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP and reporter assay; single lab","pmids":["32412910"],"is_preprint":false},{"year":2023,"finding":"The FGFR1-MEK-ERK2 signaling pathway upregulates FOXQ1 gene expression through c-FOS binding to the FOXQ1 promoter. ERK2 (but not ERK1) is specifically required; ERK2 knockout suppresses FGFR1-stimulated FOXQ1 expression, and ectopic FOXQ1 rescues FGFR1-stimulated cell growth in ERK2-KO cells.","method":"MEK/ERK inhibitors, ERK1 and ERK2 CRISPR knockout, ChIP for c-FOS at FOXQ1 promoter, FOXQ1 rescue experiment, xenograft tumor growth","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP plus genetic epistasis (ERK1/ERK2 KO) and rescue; multiple orthogonal methods; single lab","pmids":["36778115"],"is_preprint":false},{"year":2023,"finding":"HNRNPA2B1 binds m6A-modified FOXQ1 mRNA and enhances its stability, increasing FOXQ1 protein expression. Silencing HNRNPA2B1 reduces FOXQ1 protein levels and suppresses OSCC malignant phenotypes.","method":"m6A site prediction, RIP/Co-IP for HNRNPA2B1-FOXQ1 mRNA interaction, mRNA stability assay, HNRNPA2B1 knockdown and overexpression, xenograft model","journal":"IUBMB life","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirming direct RNA-protein binding with functional consequences; single lab","pmids":["38265150"],"is_preprint":false},{"year":2023,"finding":"FOXQ1 expression is maintained by SIRT4-mediated metabolic control via the FOXQ1-SIRT4-GDH axis. FOXQ1 maintains SIRT4 expression; SIRT4 suppresses GDH via ADP-ribosylation. During senescence, FOXQ1 and SIRT4 decrease, causing increased GDH activity that produces α-KG, leading to H3K9me3 erasure at IL-6/IL-8 promoters and driving SASP.","method":"GDH activity assay in aged mice and senescent fibroblasts, FOXQ1/SIRT4 expression manipulation, ChIP for H3K9me3 at IL-6/IL-8 promoters, GDH pharmacological inhibition, α-KG metabolite measurement","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple gain/loss-of-function experiments with epigenetic readout; single lab","pmids":["37516739"],"is_preprint":false},{"year":2024,"finding":"PARP1 stabilizes FOXQ1 protein by inhibiting its ubiquitination via the E3 ubiquitin ligase CHIP (STUB1), thereby protecting FOXQ1 from proteolytic degradation. Stabilized FOXQ1 activates LAMB3 transcription (ChIP-seq and luciferase assay), activating the WNT/β-catenin pathway to promote ovarian cancer progression.","method":"Co-IP of PARP1 and FOXQ1, mass spectrometry, in vivo ubiquitination assay, ChIP-seq, luciferase assay for LAMB3 promoter, PARP inhibitor experiments, xenograft and clinical samples","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP/MS, ubiquitination assay, ChIP-seq, reporter assay, in vivo drug treatment; multiple orthogonal methods in single study","pmids":["38297082"],"is_preprint":false},{"year":2024,"finding":"JNK1 directly phosphorylates FOXQ1 at serine 248 in HCC cells in response to sorafenib. Phosphorylated FOXQ1 gains high affinity for the ETHE1 promoter and activates ETHE1 transcription. ETHE1 reduces intracellular lipid peroxidation and iron levels, thereby suppressing sorafenib-induced ferroptosis. This JNK1-FOXQ1(pS248)-ETHE1 axis mediates sorafenib resistance.","method":"In vitro kinase assay (JNK1 phosphorylating FOXQ1-S248), site-directed mutagenesis of S248, ChIP for FOXQ1 at ETHE1 promoter, flow cytometry for lipid peroxidation/iron, functional ferroptosis assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus ChIP; multiple orthogonal methods; single lab","pmids":["38839744"],"is_preprint":false},{"year":2024,"finding":"p53 is a negative transcriptional regulator of FOXQ1. p53 binds close to the FOXQ1 transcription start site and suppresses FOXQ1 expression. Pharmacological p53 activation (nutlin-3 or doxorubicin) reduces FOXQ1 mRNA and protein in cancer cells with wild-type p53; p53 mutations are associated with elevated FOXQ1 expression in human cancers.","method":"CRISPR-Cas9-based genomic locus proteomics to identify p53 as FOXQ1 regulator, ChIP-qPCR for p53 at FOXQ1 promoter, luciferase reporter assay, p53 gain/loss-of-function, nutlin-3 and doxorubicin pharmacological treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — CRISPR genomic locus proteomics plus ChIP plus reporter assay plus gain/loss-of-function plus pharmacological validation; multiple orthogonal methods","pmids":["38432629"],"is_preprint":false},{"year":2024,"finding":"FOXQ1 regulates brain endothelial cell mitochondrial function through two direct mechanisms: (1) regulation of calcium signaling via huntingtin-associated protein (HAP1)-mediated ER-mitochondria calcium transfer, and (2) regulation of mitochondrial cristae integrity via ADCK1-dependent cristae organization. Endothelial-specific Foxq1 conditional knockout causes disrupted cristae morphology, reduced oxygen consumption, and impaired ATP production.","method":"Endothelial-specific conditional Foxq1 knockout, comparative transcriptomics, mitochondrial function assays (oxygen consumption, ATP production), electron microscopy for cristae, calcium imaging, identification of HAP1 and ADCK1 as direct targets","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — conditional knockout with defined organelle phenotype plus mechanistic target identification; multiple methods; single lab","pmids":["40884816"],"is_preprint":false},{"year":2024,"finding":"Foxq1 alleviates postoperative cognitive dysfunction by activating the cannabinoid receptor CB2R, with oleamide as a mediator. Foxq1 overexpression (AAV) or oleamide administration improve cognitive performance and reduce hippocampal neuroinflammation; these effects are blocked by CB2R antagonist AM630.","method":"AAV-mediated hippocampal Foxq1 overexpression, oleamide administration, CB2R antagonist (AM630) rescue experiment, behavioral tests, inflammatory cytokine measurement, transcriptomic/metabolomic analysis","journal":"Brain pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with CB2R antagonist and genetic gain-of-function; single lab","pmids":["39046224"],"is_preprint":false},{"year":2024,"finding":"Foxq1 promotes alveolar epithelial cell death in acute lung injury through Tle1-mediated inhibition of the NF-κB/Bcl2/Bax signaling pathway. Foxq1 knockdown promotes cell survival while overexpression has the opposite effect, with Tle1 identified as a mediating partner.","method":"LPS-induced ALI mouse model, Foxq1 knockdown and overexpression in MLE-12 cells, western blot for NF-κB/Bcl2/Bax, Tle1 functional assays","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss/gain-of-function with defined pathway readout; single lab","pmids":["38574238"],"is_preprint":false},{"year":2025,"finding":"p300 acetylates FOXQ1 at Lys190, enabling recognition and binding by BRD4. The resulting FOXQ1-p300-BRD4-RNA Pol II complex binds super-enhancer regions of target oncogenes, and acetylation at Lys190 directly enhances FOXQ1 binding affinity to super-enhancers, driving CRC proliferation and metastasis.","method":"ChIP-seq for FOXQ1 and BRD4 at super-enhancers, Co-IP of FOXQ1 complex, acetylation site mapping (Lys190), site-directed mutagenesis, luciferase reporter assay, in vitro and in vivo functional assays","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP-seq plus Co-IP plus site-specific mutagenesis identifying acetylation-dependent complex; multiple orthogonal methods; single lab","pmids":["40624346"],"is_preprint":false}],"current_model":"FOXQ1 is a forkhead transcription factor that drives epithelial-mesenchymal transition and metastasis by directly binding target gene promoters (E-cadherin/CDH1, TWIST1, Sox12, EGFR, LDHA, NDUFS1/NDUFV1, SIRT1, NRXN3) and recruiting transcriptional coactivators including the MLL/KMT2 histone methyltransferase complex via a direct interaction between its forkhead domain and RbBP5; its transcriptional output is context-dependent—acting as an oncogene in carcinomas (where it activates CDH2/N-cadherin in concert with nuclear β-catenin over TLE) but as a tumor suppressor in melanoma (where the lower β-catenin/TLE ratio causes CDH2 repression); FOXQ1 protein stability is post-translationally regulated by USP10-mediated deubiquitination, STUB1-mediated K63-linked polyubiquitination, PARP1-mediated protection from CHIP-dependent degradation, and JNK1-mediated phosphorylation at Ser248; upstream, FOXQ1 is transcriptionally induced by canonical Wnt signaling, TGF-β1, FGFR1-MEK-ERK2-c-FOS, and KSHV lytic factors, and is repressed by p53 and FOXF2/NCoR1/HDAC3; in metabolic contexts FOXQ1 regulates hepatic gluconeogenesis by blocking FOXO1, Sertoli cell lactate production via LDHA, and brain endothelial mitochondrial function via HAP1 and ADCK1."},"narrative":{"mechanistic_narrative":"FOXQ1 is a forkhead/winged-helix transcription factor that acts as a sequence-specific, context-dependent regulator of cell differentiation, epithelial-mesenchymal transition (EMT), and metabolism by binding forkhead consensus elements in target gene promoters and recruiting chromatin-modifying coactivators [PMID:11876636, PMID:21285253, PMID:21346143, PMID:36319643]. Its developmental and physiological roles were established in mice, where loss-of-function disrupts hair medulla differentiation (downstream of HOXC13) and abrogates secretagogue-stimulated gastric acid secretion [PMID:11309849, PMID:16835220, PMID:18544931]. In carcinomas FOXQ1 functions as an oncogene driving EMT, invasion, and metastasis, repressing the epithelial adhesion gene CDH1/E-cadherin while activating pro-metastatic programs through direct promoter binding of TWIST1, Sox12, and EGFR [PMID:21285253, PMID:21346143, PMID:23723077, PMID:25704764, PMID:33875643]. Mechanistically, FOXQ1 initiates EMT transcription by recruiting the MLL/KMT2 histone methyltransferase complex via a direct interaction between its forkhead domain and the core subunit RbBP5, driving H3K4me3 deposition at EMT gene promoters [PMID:36319643], and acetylation of FOXQ1 at Lys190 by p300 enables BRD4 recognition and assembly of a super-enhancer-bound FOXQ1-p300-BRD4-RNA Pol II complex [PMID:40624346]. FOXQ1 transcriptional output is gated by the nuclear β-catenin/TLE ratio, which switches it between an oncogenic CDH2/N-cadherin activator in carcinomas and a tumor-suppressive CDH2 repressor in melanoma, where it instead promotes differentiation by directly activating MITF [PMID:28930679, PMID:29463842, PMID:36124643]. Beyond cancer, FOXQ1 controls metabolism: it blocks FOXO1 to limit hepatic gluconeogenesis, transactivates LDHA to drive lactate production in Sertoli cells and glycolysis in tumor cells, regulates electron transport chain Complex I subunits NDUFS1/NDUFV1, and governs brain endothelial mitochondrial function via HAP1 and ADCK1 [PMID:27421728, PMID:34939230, PMID:34091745, PMID:37875474, PMID:40884816]. FOXQ1 abundance is set transcriptionally by inducers including canonical Wnt signaling, TGF-β1, FGFR1-MEK-ERK2-c-FOS, and KSHV lytic factors and by repressors p53 and FOXF2/NCoR1/HDAC3, and post-translationally by USP10 deubiquitination, STUB1-mediated K63 polyubiquitination, PARP1-mediated protection from CHIP degradation, and JNK1 phosphorylation at Ser248, alongside mRNA stabilization by HuR and HNRNPA2B1 [PMID:21285253, PMID:21346143, PMID:23555880, PMID:30807702, PMID:32332873, PMID:36575252, PMID:38960057, PMID:36778115, PMID:38297082, PMID:38839744, PMID:38432629].","teleology":[{"year":2001,"claim":"Established that FOXQ1 is a functionally required winged-helix transcription factor in vivo, answering whether the gene has a non-redundant developmental role.","evidence":"Genetic mapping of satin mice with an intragenic deletion and an ENU missense mutation in the DNA-binding domain producing identical hair medulla differentiation defects","pmids":["11309849"],"confidence":"High","gaps":["Did not identify direct transcriptional targets in hair follicle","Mechanism of medulla cell differentiation downstream not defined"]},{"year":2002,"claim":"Defined the molecular basis of FOXQ1 DNA recognition, showing its winged-helix domain adopts DNA-bound conformations distinct from a close relative.","evidence":"Heteronuclear NMR structure of the HFH-1 DNA-binding domain free and DNA-bound, compared with Genesis","pmids":["11876636"],"confidence":"High","gaps":["No full-length structure or cofactor-bound complex","Does not address activation versus repression determinants"]},{"year":2006,"claim":"Placed FOXQ1 in a defined differentiation hierarchy as a direct HOXC13 target, explaining its developmental regulation.","evidence":"ChIP, reporter assays, and genetic epistasis in Hoxc13-transgenic and satin mice","pmids":["16835220"],"confidence":"High","gaps":["Direct FOXQ1 targets in medulla program not enumerated"]},{"year":2008,"claim":"Demonstrated a distinct physiological role in gastric acid secretion, broadening FOXQ1 function beyond hair.","evidence":"Foxq1 knockout mice with acid secretion assays and ultrastructural analysis of parietal cells","pmids":["18544931"],"confidence":"High","gaps":["Transcriptional targets controlling tubulovesicle-membrane fusion unknown"]},{"year":2011,"claim":"Identified FOXQ1 as a driver of EMT and metastasis through direct CDH1/E-cadherin repression, establishing its oncogenic transcriptional program; independently replicated across two labs.","evidence":"ChIP/promoter binding at the CDH1 E-box, RNAi and ectopic expression, in vivo lung metastasis, TGF-β1 induction","pmids":["21285253","21346143","20717954"],"confidence":"High","gaps":["Coactivator/corepressor machinery not yet defined","Mechanism of E-box repression not structurally resolved"]},{"year":2013,"claim":"Expanded the FOXQ1 oncogenic target repertoire and positioned it within Wnt signaling, showing it both responds to and propagates pro-metastatic transcription.","evidence":"ChIP/reporter assays defining direct binding to TWIST1, NRXN3, and Wnt-responsive elements in the FOXQ1 promoter across CRC and glioma models","pmids":["23723077","23383267","23555880"],"confidence":"High","gaps":["Whether FOXQ1 acts as activator or repressor at a given promoter context-dependently not resolved here"]},{"year":2014,"claim":"Built out tumor-promoting axes and a TGF-β1/FOXQ1 feedback loop, linking FOXQ1 to stemness and chemoresistance.","evidence":"ChIP/site-directed mutagenesis (Sox12), PDGFR epistasis, and TGF-β1 promoter ChIP with functional EMT assays","pmids":["25704764","25502837","25287361"],"confidence":"High","gaps":["Direct versus indirect activation of some targets (PDGFRs) not fully separated","TGF-β1 target claim rests on a single ChIP method"]},{"year":2016,"claim":"Connected FOXQ1 to β-catenin nuclear translocation and to senescence/inflammation control via SIRT1, broadening its signaling and homeostatic roles.","evidence":"β-catenin fractionation/immunofluorescence with TGF-β1 stimulation; ChIP at SIRT1 promoter with cytokine and senescence readouts","pmids":["25955104","28726780"],"confidence":"High","gaps":["No direct FOXQ1-β-catenin binding assay in the CRC crosstalk study","Whether SIRT1 axis operates in cancer as in fibroblasts not addressed"]},{"year":2016,"claim":"Defined a metabolic, non-cancer role for hepatic FOXQ1 in gluconeogenesis through a protein-protein interaction with FOXO1.","evidence":"Co-IP of FOXQ1-FOXO1, primary hepatocyte and in vivo gain/loss-of-function with glucose tolerance tests","pmids":["27421728"],"confidence":"High","gaps":["Structural basis of FOXQ1-FOXO1 interaction unknown","Whether FOXQ1 displaces FOXO1 directly at all gluconeogenic promoters not mapped"]},{"year":2017,"claim":"Revealed lineage-specific functional reversal, establishing that the nuclear β-catenin/TLE ratio switches FOXQ1 between CDH2 activator (carcinoma oncogene) and repressor (melanoma suppressor).","evidence":"Reciprocal Co-IP of FOXQ1 with β-catenin and TLE, β-catenin/TLE manipulation, in vivo metastasis models","pmids":["28930679"],"confidence":"High","gaps":["Quantitative threshold of the β-catenin/TLE ratio not defined","How TLE binding mechanistically converts activation to repression not resolved"]},{"year":2018,"claim":"Showed FOXQ1 directly drives melanocyte differentiation by activating MITF via cAMP/CREB1, consistent with its tumor-suppressive role in melanoma.","evidence":"ChIP/reporter at MITF, cAMP/CREB1 activation, BRAFV600E models, in vivo pigmentation","pmids":["29463842"],"confidence":"High","gaps":["Reconciliation of MITF activation with EMT repression in same lineage not fully detailed"]},{"year":2019,"claim":"Identified an upstream repressive mechanism: FOXF2 recruits NCoR1/HDAC3 to the FOXQ1 promoter, defining transcriptional control of FOXQ1 levels.","evidence":"ChIP showing NCoR1/HDAC3 recruitment, reporter assays, gain/loss-of-function in basal-like breast cancer","pmids":["30807702"],"confidence":"High","gaps":["Whether FOXF2-FOXQ1 mutual repression operates outside breast cancer untested"]},{"year":2020,"claim":"Established post-transcriptional control of FOXQ1 by RNA-binding proteins and added a Wnt-promoting role in osteogenesis via ANXA2.","evidence":"RIP showing HuR binding/stabilizing FOXQ1 mRNA with KH-3 disruption; Co-IP/MS identifying ANXA2 with β-catenin functional rescue; NAC1-BCL6 complex ChIP at FOXQ1 promoter","pmids":["32332873","32943107","32412910"],"confidence":"High","gaps":["m6A/sequence determinants of HuR binding not mapped here","ANXA2-FOXQ1 mechanism of β-catenin activation indirect"]},{"year":2021,"claim":"Defined FOXQ1 as a direct transcriptional regulator of cellular metabolism, controlling oxidative phosphorylation and lactate production through direct promoter binding.","evidence":"ChIP at NDUFS1/NDUFV1 with Complex I and Seahorse assays; ChIP at Ldha in Foxq1-knockout Sertoli cells with lactate rescue and fertility phenotyping; direct EGFR promoter binding driving vasculogenic mimicry","pmids":["34939230","34091745","33875643"],"confidence":"High","gaps":["Whether metabolic versus EMT target selection is co-regulated unknown","Tissue-specific cofactor requirements for metabolic targets undefined"]},{"year":2022,"claim":"Resolved the central coactivator mechanism: FOXQ1 recruits the MLL/KMT2 complex via a direct forkhead-domain–RbBP5 interaction to deposit H3K4me3 and initiate EMT, and acts as a differential Wnt target activator resembling TCF7L1.","evidence":"Co-IP with domain-mapping mutagenesis, H3K4me3 ChIP-seq, pharmacologic KMT2 inhibition, in vivo progression; RNA-seq/ChIP comparing cofactor recruitment with TCF7L1; shared DDR2 effector with SNAI1; STUB1 K63-ubiquitination of FOXQ1; SIRT1/β-catenin radioresistance axis","pmids":["36319643","36124643","36713812","36575252","35183223"],"confidence":"High","gaps":["Structure of the FOXQ1-RbBP5/MLL complex not solved","How acetylation/phosphorylation states feed into MLL recruitment unknown"]},{"year":2023,"claim":"Mapped a multi-layered regulatory network setting FOXQ1 levels and activity—upstream kinase, viral, and tumor-suppressor inputs plus mRNA stabilization—and linked FOXQ1 to ferroptosis and metabolic-epigenetic aging axes.","evidence":"ChIP for c-FOS at FOXQ1 (FGFR1-MEK-ERK2); ORF45-RSK induction in KSHV; HNRNPA2B1 m6A-dependent mRNA stabilization; SIRT4-GDH-α-KG/H3K9me3 SASP axis; LDHA-driven glycolysis; circ_0000643/miR-153/SLC7A11 ferroptosis suppression; USP10 deubiquitination stabilizing FOXQ1; NDRG1/stellate-cell feedback","pmids":["36778115","36815831","38265150","37516739","37875474","37591453","38960057","29248714"],"confidence":"High","gaps":["Hierarchy and crosstalk among the many input pathways not integrated","Several axes (ferroptosis, SASP) rest on single-lab data"]},{"year":2024,"claim":"Defined post-translational and transcriptional control nodes governing FOXQ1 stability and target specificity, and extended its role to brain endothelial mitochondrial function and CNS protection.","evidence":"PARP1 Co-IP/MS and ubiquitination assays protecting FOXQ1 from CHIP; JNK1 in vitro kinase assay phosphorylating Ser248 to redirect FOXQ1 to ETHE1 (ferroptosis/sorafenib resistance); p53 CRISPR genomic-locus proteomics and ChIP repressing FOXQ1; endothelial conditional knockout defining HAP1/ADCK1 mitochondrial targets; CB2R/oleamide cognitive role; Tle1-NF-κB lung injury axis","pmids":["38297082","38839744","38432629","40884816","39046224","38574238"],"confidence":"High","gaps":["How phosphorylation at Ser248 reprograms genome-wide binding not mapped","Interplay between PARP1, STUB1, USP10, and CHIP in setting FOXQ1 half-life not integrated"]},{"year":2025,"claim":"Showed acetylation-dependent assembly of a super-enhancer-bound FOXQ1 complex, providing a chromatin mechanism for its potent oncogenic output.","evidence":"p300 acetylation of FOXQ1 Lys190, BRD4 recognition, FOXQ1-p300-BRD4-RNA Pol II ChIP-seq at super-enhancers with site-directed mutagenesis","pmids":["40624346"],"confidence":"High","gaps":["Relationship between Lys190 acetylation and MLL/RbBP5 recruitment unresolved","Genome-wide super-enhancer target set not exhaustively defined"]},{"year":null,"claim":"It remains unresolved how the combinatorial post-translational code (acetylation, phosphorylation, ubiquitination) and cofactor ratio (β-catenin/TLE, MLL, p300/BRD4) are integrated to select activating versus repressive target programs in a given cell type.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking FOXQ1 modification state to genome-wide target choice","No high-resolution structure of FOXQ1 in cofactor complexes","Context determinants of oncogene-versus-suppressor switch not generalized beyond melanoma/carcinoma"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,7,10,13,23,26,31,32,33,36,53]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,2,7,31,32,33]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,23,34,53]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,10,13,31,32,33,34,53]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,16,23,30,36]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[19,31,32,40,50]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[34,46,53]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,4,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,23,47,48]}],"complexes":["MLL/KMT2 histone methyltransferase complex","FOXQ1-p300-BRD4-RNA Pol II super-enhancer complex"],"partners":["RBBP5","CTNNB1","TLE","FOXO1","STUB1","USP10","PARP1","P300"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C009","full_name":"Forkhead box protein Q1","aliases":["HNF-3/forkhead-like protein 1","HFH-1","Hepatocyte nuclear factor 3 forkhead homolog 1"],"length_aa":403,"mass_kda":41.5,"function":"Plays a role in hair follicle differentiation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9C009/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FOXQ1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FOXQ1","total_profiled":1310},"omim":[{"mim_id":"612788","title":"FORKHEAD BOX Q1; FOXQ1","url":"https://www.omim.org/entry/612788"},{"mim_id":"612582","title":"CHROMOSOME 6pter-p24 DELETION SYNDROME","url":"https://www.omim.org/entry/612582"},{"mim_id":"601090","title":"FORKHEAD BOX C1; FOXC1","url":"https://www.omim.org/entry/601090"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"stomach 1","ntpm":101.2},{"tissue":"urinary bladder","ntpm":50.0}],"url":"https://www.proteinatlas.org/search/FOXQ1"},"hgnc":{"alias_symbol":["HFH1"],"prev_symbol":[]},"alphafold":{"accession":"Q9C009","domains":[{"cath_id":"1.10.10.10","chopping":"125-197","consensus_level":"high","plddt":93.9878,"start":125,"end":197}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C009","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C009-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C009-F1-predicted_aligned_error_v6.png","plddt_mean":60.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FOXQ1","jax_strain_url":"https://www.jax.org/strain/search?query=FOXQ1"},"sequence":{"accession":"Q9C009","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C009.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C009/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C009"}},"corpus_meta":[{"pmid":"20145154","id":"PMC_20145154","title":"FOXQ1 is overexpressed in colorectal cancer and enhances tumorigenicity and tumor growth.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20145154","citation_count":166,"is_preprint":false},{"pmid":"32061262","id":"PMC_32061262","title":"Circular RNA CRIM1 functions as a ceRNA to promote nasopharyngeal carcinoma metastasis and docetaxel chemoresistance through upregulating FOXQ1.","date":"2020","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32061262","citation_count":166,"is_preprint":false},{"pmid":"21285253","id":"PMC_21285253","title":"Forkhead transcription factor foxq1 promotes epithelial-mesenchymal transition and breast cancer metastasis.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21285253","citation_count":161,"is_preprint":false},{"pmid":"21346143","id":"PMC_21346143","title":"FOXQ1 regulates epithelial-mesenchymal transition in human cancers.","date":"2011","source":"Cancer 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axis.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38292422","citation_count":4,"is_preprint":false},{"pmid":"28580309","id":"PMC_28580309","title":"Up-Regulation of FOXC2 and FOXQ1 Is Associated with The Progression of Gastric-Type Adenocarcinoma.","date":"2017","source":"Cell journal","url":"https://pubmed.ncbi.nlm.nih.gov/28580309","citation_count":4,"is_preprint":false},{"pmid":"34496413","id":"PMC_34496413","title":"Downregulation of miR-519d-3p is Associated with Poor Outcomes and Facilitates Tumor Progression in Papillary Thyroid Cancer by Regulating FOXQ1.","date":"2021","source":"Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme","url":"https://pubmed.ncbi.nlm.nih.gov/34496413","citation_count":4,"is_preprint":false},{"pmid":"37870056","id":"PMC_37870056","title":"Hsa_circ_0001687 Function as a ceRNA to Facilitate Hepatocellular Carcinoma Progression via miR-140- 3p/FOXQ1 Axis.","date":"2023","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/37870056","citation_count":3,"is_preprint":false},{"pmid":"39046224","id":"PMC_39046224","title":"Foxq1 activates CB2R with oleamide to alleviate POCD.","date":"2024","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39046224","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50777,"output_tokens":13809,"usd":0.179733,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":26045,"output_tokens":6532,"usd":0.146762,"stage2_stop_reason":"end_turn"},"total_usd":0.326495,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"FOXQ1 (HFH-1) is mutant in satin (sa) mice, which display structurally abnormal medulla cells and defects in hair shaft differentiation. A missense mutation in the conserved winged helix DNA-binding domain causes the same phenotype as an intragenic deletion, establishing FOXQ1 as required for hair medulla differentiation.\",\n      \"method\": \"Genetic mapping, identification of intragenic deletion and ENU-induced missense mutation in DNA-binding domain, phenotypic characterization of homozygous mutants\",\n      \"journal\": \"Genesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two independent alleles (deletion and missense in DNA-binding domain) produce identical phenotype, establishing causality; replicated across alleles\",\n      \"pmids\": [\"11309849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HFH-1 (FOXQ1) represses transcription of smooth muscle-specific promoters (telokin, SM22α) by binding to a forkhead consensus site in an AT-rich region of the telokin promoter. The DNA-binding domain alone is sufficient for repression, and HFH-1 does not disrupt serum response factor binding to adjacent CArG boxes, indicating it blocks other positive-acting factors.\",\n      \"method\": \"Reporter gene (promoter-luciferase) assays in A10 vascular smooth muscle cells, overexpression of HFH-1 and DNA-binding domain alone, gel-shift/footprint to map binding site\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro transcription assay with domain-deletion mapping, multiple promoter targets tested, single lab\",\n      \"pmids\": [\"10896677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The DNA-binding domain of HFH-1 (FOXQ1) adopts a winged-helix fold that forms DNA complexes with different local conformations than the closely related Genesis protein when contacting the same DNA sequence, as determined by heteronuclear NMR.\",\n      \"method\": \"Heteronuclear NMR structure determination of HFH-1 DNA-binding domain in free and DNA-bound states; structural comparison with Genesis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional comparison; single lab but direct structural method\",\n      \"pmids\": [\"11876636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The human FOXQ1 gene encodes a 403-amino acid protein with a conserved HNF-3/forkhead DNA-binding domain (100% identity with mouse and rat) and two putative transcriptional activation domains. The gene is expressed predominantly in stomach, trachea, bladder, and salivary gland.\",\n      \"method\": \"Isolation and sequencing of human genomic and cDNA clones; sequence alignment; tissue expression by Northern/RT-PCR\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cDNA characterization and domain annotation; single lab but foundational molecular characterization\",\n      \"pmids\": [\"11747606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FOXQ1 is a direct downstream transcriptional target of HOXC13 during hair follicle medulla differentiation. HOXC13 binds the Foxq1 promoter and activates its expression, as shown by DNA binding studies, co-transfection reporter assays, and ChIP. Expression of additional medulla-specific genes depends on functional Foxq1, placing FOXQ1 downstream of HOXC13 in a hair differentiation pathway.\",\n      \"method\": \"ChIP assay, co-transfection/reporter assay, gene array in Hoxc13-transgenic mice, validation in satin (Foxq1-mutant) mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP plus reporter assay plus genetic epistasis (satin mouse), multiple orthogonal methods in one study\",\n      \"pmids\": [\"16835220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FOXQ1 is required for gastric acid secretion in mice. Foxq1-deficient mice lack gastric acid secretion in response to secretagogue stimuli despite normal parietal cell development; ultrastructural analysis suggests impaired fusion of cytoplasmic tubulovesicles with the apical membrane of secretory canaliculi.\",\n      \"method\": \"Foxq1 knockout mouse model, gastric acid secretion assays with secretagogues, transmission electron microscopy, parietal cell morphology analysis\",\n      \"journal\": \"Cytogenetic and genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — loss-of-function (knockout) with specific functional readout (acid secretion) and ultrastructural mechanism; single lab\",\n      \"pmids\": [\"18544931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FOXQ1 transcriptionally activates p21(CIP1/WAF1) by binding to its promoter, as shown by reporter assay and ChIP. FOXQ1 overexpression also upregulates VEGFA, WNT3A, RSPO2, and BCL11A, mediating angiogenic and antiapoptotic effects in vivo.\",\n      \"method\": \"siRNA knockdown microarray analysis, luciferase reporter assay, chromatin immunoprecipitation (ChIP), stable overexpression xenograft model, CD31 and TUNEL staining\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP plus reporter assay identifying direct transcriptional target, supported by in vivo xenograft data; single lab\",\n      \"pmids\": [\"20145154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FOXQ1 promotes EMT and breast cancer metastasis by directly repressing E-cadherin (CDH1) expression through binding to the E-box in its promoter region. FOXQ1 expression is induced by TGF-β1, and FOXQ1 knockdown blocks TGF-β1-induced EMT.\",\n      \"method\": \"Ectopic expression and shRNA knockdown, in vitro migration/invasion assays, in vivo lung metastasis model, ChIP and promoter binding assay for E-cadherin E-box\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP demonstrating direct promoter binding, genetic loss-of-function, and in vivo metastasis model; replicated in parallel by a second group (PMID 21346143)\",\n      \"pmids\": [\"21285253\", \"21346143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FOXQ1 promotes EMT in breast cancer cells; RNAi suppression of FOXQ1 reverses EMT, and enforced FOXQ1 expression induces EMT in differentiated human mammary epithelial cells associated with transcriptional inactivation of E-cadherin (CDH1).\",\n      \"method\": \"RNAi knockdown, ectopic expression, 3D Matrigel culture, CDH1 promoter reporter assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independent replication of FOXQ1-CDH1 repression with multiple orthogonal methods across two labs (PMID 21285253 and 21346143)\",\n      \"pmids\": [\"21346143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Repression of FoxQ1 in mammary epithelial cells increases E-cadherin expression, promotes cell-cell contacts, rearranges the actin cytoskeleton, slows G1-phase cell cycle progression, and enhances migration of coherent epithelial sheets. FoxQ1 was identified as a downstream mediator of TGF-β1-induced gene expression changes including Ets-1, Zeb1, and Zeb2.\",\n      \"method\": \"FoxQ1 knockdown by RNAi, cell morphology analysis, gene expression profiling, cell cycle analysis by flow cytometry, migration assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes and gene expression profiling; single lab\",\n      \"pmids\": [\"20717954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FOXQ1 directly binds the TWIST1 promoter and transcriptionally activates TWIST1 expression, thereby modulating TWIST1-dependent metastatic phenotypes in colorectal cancer cells. Enhanced FOXQ1 expression increased migration, invasion, and distant metastasis in a chicken chorioallantoic membrane model.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, forced expression and RNA silencing, in vivo chorioallantoic membrane metastasis assay\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP plus reporter assay demonstrating direct promoter binding of TWIST1 by FOXQ1; supported by in vivo metastasis model\",\n      \"pmids\": [\"23723077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FoxQ1 directly binds the NRXN3 promoter and represses its transcriptional activity, promoting glioma cell proliferation and migration. Knockdown of FoxQ1 reduces these behaviors, while NRXN3 expression is negatively correlated with FoxQ1 in glioma tissues.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, stable FoxQ1 knockdown and overexpression cell lines, MTT proliferation assay, transwell migration assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP and reporter assay with functional validation; single lab\",\n      \"pmids\": [\"23383267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FOXQ1 is a direct transcriptional target of canonical Wnt signaling. FOXQ1 promoter contains Wnt-responsive elements, and Wnt pathway activation induces FOXQ1 expression as demonstrated by ChIP and luciferase reporter assays.\",\n      \"method\": \"ChIP, luciferase reporter assay, qRT-PCR and western blot in Wnt-stimulated CRC cell lines and laser microdissected human biopsies\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP and reporter assays directly demonstrating Wnt-responsive element occupancy; single lab but multiple methods\",\n      \"pmids\": [\"23555880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FOXQ1 directly binds the Sox12 promoter and transactivates Sox12 expression in hepatocellular carcinoma. Sox12 in turn activates Twist1 and FGFBP1 transcription to promote HCC invasion and metastasis, placing FOXQ1 upstream of the Sox12-Twist1/FGFBP1 axis.\",\n      \"method\": \"Serial deletion, site-directed mutagenesis, and ChIP assays on Sox12 promoter; siRNA knockdown and rescue experiments; in vivo metastasis models\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP plus site-directed mutagenesis of promoter plus functional rescue in vivo; single lab\",\n      \"pmids\": [\"25704764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Foxq1 promotes breast cancer stemness traits and chemoresistance by transcriptionally activating PDGFRα and PDGFRβ directly or indirectly through the Foxq1/Twist1 axis. Knockdown of both PDGFRα and β reverses Foxq1-promoted oncogenesis more effectively than either alone; PDGFRβ is the more potent mediator of Foxq1-promoted stemness.\",\n      \"method\": \"Expression profiling, siRNA knockdown, pharmacological PDGFR inhibition, in vitro stemness assays, in vivo xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological epistasis, in vivo validation; single lab\",\n      \"pmids\": [\"25502837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FOXQ1 directly binds the TGF-β1 promoter (E-cadherin and N-cadherin promoter regions confirmed by ChIP) and activates TGF-β1 expression, and TGF-β1 in turn upregulates FOXQ1, forming a positive feedback loop that drives EMT.\",\n      \"method\": \"ChIP assay, shRNA knockdown, wound healing and invasion assays, RT-PCR\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP assay supporting direct binding; single lab, single ChIP method for TGF-β1 target claim\",\n      \"pmids\": [\"25287361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOXQ1 silencing in colorectal cancer cells prevents nuclear translocation of β-catenin, thereby reducing Wnt signaling activity. Additionally, TGF-β1 induces FOXQ1 expression and promotes cancer cell migration/invasion via FOXQ1, placing FOXQ1 as a mediator of crosstalk between TGF-β and Wnt signaling pathways.\",\n      \"method\": \"siRNA knockdown, β-catenin nuclear fractionation and immunofluorescence, in vitro invasion/migration assays, TGF-β1 stimulation\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear fractionation and functional assays; single lab, no direct binding assay for β-catenin\",\n      \"pmids\": [\"25955104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOXQ1 transcriptionally represses CDH1 (E-cadherin) in esophageal cancer by binding to its promoter as a transcriptional repressor, promoting cell proliferation and metastasis. CDH1 silencing rescues migratory ability lost by FOXQ1 knockdown.\",\n      \"method\": \"Reporter gene assay, RT-PCR, western blot, overexpression and knockdown, migration chamber assay, rescue experiment\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with rescue experiment; single lab\",\n      \"pmids\": [\"26349968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOXQ1 directly binds the SIRT1 promoter and transcriptionally upregulates SIRT1, which in turn inhibits NF-κB-driven expression of inflammatory cytokines IL-6 and IL-8. This FOXQ1-SIRT1 axis suppresses replicative senescence in human fibroblasts.\",\n      \"method\": \"ChIP assay demonstrating FOXQ1 binding to SIRT1 promoter, FOXQ1 overexpression and knockdown, cytokine measurement, senescence assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP plus functional phenotype with defined downstream pathway (SIRT1-NF-κB); single lab, multiple methods\",\n      \"pmids\": [\"28726780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Hepatic FOXQ1 regulates gluconeogenesis by interacting with FOXO1 and blocking its binding to insulin response elements in gluconeogenic gene promoters. FOXQ1 rescue in diabetic mice decreases blood glucose; FOXQ1 deficiency increases blood glucose and impairs glucose tolerance.\",\n      \"method\": \"Primary hepatocyte overexpression/deficiency, in vivo FOXQ1 hepatic rescue in db/db and HFD-obese mice, glucose tolerance tests, co-immunoprecipitation of FOXQ1-FOXO1 interaction, promoter binding assays\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — Co-IP identifying FOXQ1-FOXO1 interaction, in vivo loss- and gain-of-function with defined metabolic phenotype; single lab\",\n      \"pmids\": [\"27421728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOXQ1 promotes colorectal cancer cell migration and invasion through activation of PI3K/AKT signaling. FOXQ1 knockdown reduces phosphorylated FAK, PI3K, and AKT levels as well as MMP-2/9 expression.\",\n      \"method\": \"siRNA knockdown, western blot for signaling components, migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — western blot for pathway components without direct binding/epistasis experiment; single lab, single method\",\n      \"pmids\": [\"28559972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOXQ1 regulates prostate cancer cell proliferation and apoptosis by controlling BCL11A and MDM2 expression. Overexpression of BCL11A reverses the pro-apoptotic effects of FOXQ1 inhibition and restores MDM2 expression, placing BCL11A downstream of FOXQ1.\",\n      \"method\": \"siRNA knockdown, BCL11A overexpression rescue assay, flow cytometry apoptosis, western blot\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment placing BCL11A in FOXQ1 pathway; single lab\",\n      \"pmids\": [\"27573292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXQ1 directly binds the NDRG1 promoter and transactivates NDRG1 expression in HCC, which activates pSTAT6/CCL26 signaling to recruit hepatic stellate cells and create a positive feedback loop with cancer-associated fibroblasts enhancing tumor initiation.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, Co-culture models, siRNA knockdown, in vivo HCC initiation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay with mechanistic co-culture model; single lab\",\n      \"pmids\": [\"29248714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXQ1 functions as a melanoma suppressor rather than oncogene, suppressing EMT, invasion, and metastasis in melanocyte lineage cells. This lineage-specific reversal depends on FOXQ1's ability to repress (in melanoma) rather than activate (in carcinomas) N-cadherin (CDH2) transcription. The switch is determined by the nuclear β-catenin/TLE ratio: high in carcinomas drives CDH2 activation; low in melanoma drives repression. FOXQ1 interacts with nuclear β-catenin and TLE proteins.\",\n      \"method\": \"Reciprocal Co-IP of FOXQ1 with β-catenin and TLE proteins, loss- and gain-of-function in melanoma and carcinoma cells, in vivo xenograft/metastasis models, manipulation of β-catenin and TLE levels to switch CDH2 regulation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — Co-IP identifying binding partners, mechanistic rescue by altering β-catenin/TLE ratio, in vivo validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28930679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXQ1 promotes NKTCL cell proliferation and blocks apoptosis via the Sonic Hedgehog (Shh) signaling pathway; FOXQ1 knockdown downregulates Shh pathway proteins, blocks cells in G0/G1, and increases apoptosis with elevated Bax/Caspase-3 and reduced Bcl-2. Exogenous Shh reverses the effects of FOXQ1 knockdown.\",\n      \"method\": \"shRNA knockdown, Shh pathway inhibitor (Cyclopamine) and recombinant Shh rescue, CCK-8, BrdU incorporation, flow cytometry, western blot\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic rescue epistasis; single lab\",\n      \"pmids\": [\"29132010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-4 induces FoxQ1 expression in human monocytes and macrophages. FoxQ1 overexpression in RAW264.7 monocytic cells facilitates their migration towards MCP-1 and is associated with decreased expression of migration-regulating genes claudin-11 and plexin C1, and increases TNFα secretion after LPS challenge.\",\n      \"method\": \"IL-4 stimulation of primary monocytes and macrophages, FoxQ1 overexpression in RAW cells, migration assay, RT-PCR for target genes, TNFα ELISA\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined cellular phenotype and downstream gene changes; single lab\",\n      \"pmids\": [\"29203829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXQ1 directly activates MITF gene transcription to induce differentiation in normal and transformed melanocytic cells. FOXQ1-mediated pigmentation depends on activation of the cAMP/CREB1 pathway, and FOXQ1 mediates BRAFV600E-dependent regulation of MITF levels.\",\n      \"method\": \"ChIP and promoter reporter assays for MITF, cAMP/CREB1 pathway activation experiments, BRAFV600E expression models, gain- and loss-of-function in melanocytic cells and in vivo mouse pigmentation models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP plus reporter assay demonstrating direct MITF promoter activation, in vivo mouse model; single lab\",\n      \"pmids\": [\"29463842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EWS-FLI1 cooperates with Foxq1 in mouse Ewing sarcoma through a direct protein-protein interaction (EWS portion of EWS-FLI1 binds Foxq1). Foxq1 Fox-motif binding sites are enriched within EWS-FLI1 ChIP-seq peaks. Trib1 and Nrg1 are co-regulated target genes of EWS-FLI1/Foxq1 important for cell proliferation and survival.\",\n      \"method\": \"ChIP-seq for EWS-FLI1 binding, Co-immunoprecipitation of Foxq1 with EWS-FLI1, motif analysis, target gene validation\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP-seq; single lab\",\n      \"pmids\": [\"29945296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FOXF2 and FOXQ1 engage in mutual transcriptional repression in basal-like breast cancer. FOXF2 recruits nuclear receptor corepressor 1 (NCoR1) and HDAC3 to the FOXQ1 promoter to suppress FOXQ1 transcription, whereas FOXQ1 does not use this mechanism to repress FOXF2.\",\n      \"method\": \"ChIP assay demonstrating NCoR1/HDAC3 recruitment to FOXQ1 promoter by FOXF2, luciferase reporter assays, ectopic expression and knockdown experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP identifying specific corepressor recruitment mechanism; reporter assays with gain/loss of function; single lab\",\n      \"pmids\": [\"30807702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HuR (ELAVL1) RNA-binding protein directly binds FOXQ1 mRNA and stabilizes it. The HuR inhibitor KH-3 disrupts the HuR-FOXQ1 mRNA interaction, leading to inhibition of breast cancer invasion and metastasis.\",\n      \"method\": \"RNA immunoprecipitation (RIP) identifying HuR-FOXQ1 mRNA interaction, HuR inhibitor KH-3 treatment, in vitro invasion assays, in vivo lung metastasis model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — RIP confirming direct RNA-protein interaction plus pharmacological disruption with functional readout; single lab\",\n      \"pmids\": [\"32332873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOXQ1 promotes osteogenic differentiation of bone mesenchymal stem cells (BMSCs) by promoting nuclear translocation of β-catenin and enhancing Wnt/β-catenin signaling. FOXQ1 physically interacts with Annexin A2 (ANXA2), and ANXA2 depletion reverses the FOXQ1-promoted Wnt/β-catenin activation.\",\n      \"method\": \"Lentiviral overexpression/knockdown of Foxq1, TOPFlash/FOPFlash reporter, immunofluorescence for β-catenin, Co-IP mass spectrometry identifying ANXA2 as FOXQ1-binding partner, ANXA2 siRNA rescue\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identifying binding partner with functional rescue; single lab\",\n      \"pmids\": [\"32943107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXQ1 directly regulates transcription of electron transport chain Complex I subunits NDUFS1 and NDUFV1 by binding to their promoters (ChIP). FOXQ1 overexpression increases Complex I assembly and activity, oxygen consumption, and intracellular pyruvate, lactate, and ATP levels in breast cancer cells.\",\n      \"method\": \"ChIP assay for FOXQ1 at NDUFS1 and NDUFV1 promoters, RNA-seq after FOXQ1 overexpression, Complex I activity and assembly assays, Seahorse oxygen consumption measurement\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP establishing direct promoter binding of metabolic target genes plus functional metabolic assays; single lab\",\n      \"pmids\": [\"34939230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXQ1 directly binds the LDHA gene promoter in mouse Sertoli cells and transactivates Ldha expression, thereby regulating lactate production essential for germ cell survival. Foxq1-knockout males are subfertile with oligoasthenozoospermia due to lactate deficiency; LDHA overexpression rescues lactate production in Foxq1-deficient Sertoli cells.\",\n      \"method\": \"CRISPR-Cas9 Foxq1 knockout mice, ChIP assay for FOXQ1 at Ldha promoter, lentiviral LDHA overexpression rescue, lactate measurement, fertility phenotyping\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP plus genetic knockout with defined metabolic phenotype plus rescue experiment; single lab\",\n      \"pmids\": [\"34091745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOXQ1 directly binds the EGFR promoter and transcriptionally activates EGFR expression in NPC cells, promoting vasculogenic mimicry (VM) formation and metastasis via the EGFR signaling pathway. EGFR inhibitors (Nimotuzumab or Erlotinib) block Foxq1-induced VM.\",\n      \"method\": \"Luciferase reporter gene assay, ChIP assay for Foxq1 at EGFR promoter, in vitro VM formation, in vivo metastasis model, EGFR inhibitor treatment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP plus reporter assay establishing direct EGFR promoter binding; pharmacological epistasis; single lab\",\n      \"pmids\": [\"33875643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXQ1 initiates EMT by recruiting the MLL/KMT2 histone methyltransferase complex as a transcriptional coactivator. The Forkhead box domain of FOXQ1 directly binds the MLL core complex subunit RbBP5 without disrupting FOXQ1 DNA binding. FOXQ1 promoter recognition precedes MLL complex assembly and H3K4me3 deposition at EMT gene promoters. Disruption of the FOXQ1-RbBP5 interaction or pharmacologic targeting of KMT2/MLL inhibits EMT and in vivo tumor progression.\",\n      \"method\": \"Co-IP of FOXQ1 with MLL complex subunits including RbBP5, domain-mapping mutagenesis of FOXQ1-RbBP5 interaction, ChIP-seq for H3K4me3 at EMT gene promoters, pharmacologic KMT2 inhibition, in vivo tumor progression assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP with mutagenesis, ChIP-seq, pharmacological epistasis, and in vivo validation; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"36319643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXQ1 directly binds the SIRT1 promoter and transcriptionally activates SIRT1; SIRT1 in turn enhances β-catenin expression and nuclear translocation, augmenting Wnt signaling, stemness, and radio-resistance of CRC cells.\",\n      \"method\": \"Luciferase reporter assay, Co-IP, ChIP assay for FOXQ1 at SIRT1 promoter, FOXQ1/SIRT1 knockdown and overexpression, xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP and Co-IP plus reporter assay; single lab\",\n      \"pmids\": [\"35183223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXQ1 is a differential activator of Wnt target gene expression. Upon Wnt pathway activation, FOXQ1 synergizes with the β-catenin nuclear complex to boost major Wnt targets; in parallel, FOXQ1 independently controls other Wnt target genes in a β-catenin-independent manner. FOXQ1 occupies Wnt-responsive elements in β-catenin target gene promoters and recruits a similar set of co-factors as TCF7L1.\",\n      \"method\": \"RNA-seq in CRC cell lines, ChIP for FOXQ1 at Wnt-responsive elements, comparison of co-factor recruitment with TCF7L1, FOXQ1 knockdown in Wnt-stimulated cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP plus RNA-seq plus co-factor comparison; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"36124643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXQ1 and SNAI1 act as independent EMT transcription factors sharing a common downstream target DDR2 (the most upregulated receptor tyrosine kinase). DDR2 is a shared effector mediating cell motility without significantly affecting EMT marker expression or stem cell population. DDR2 knockdown in FOXQ1-driven EMT models alters the global metabolic profile including glutamine-glutamate and aspartate recycling.\",\n      \"method\": \"Ectopic expression of FOXQ1 and SNAI1 in HMLE cells, transcriptomic analysis, DDR2 knockdown and overexpression, motility assays, metabolomics\",\n      \"journal\": \"Cancer research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomic identification plus genetic loss-of-function epistasis and metabolomics; single lab\",\n      \"pmids\": [\"36713812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STUB1 directs FOXQ1-mediated transactivation of Ldha in mouse Sertoli cells via K63-linked non-proteolytic polyubiquitination of FOXQ1, facilitating lactate production in FSH-stimulated Sertoli cells. Conditional Stub1 knockout in Sertoli cells impairs fertility due to lactate deficiency.\",\n      \"method\": \"Sertoli cell-specific Stub1 conditional knockout (Amh-Cre), ChIP assay, in vivo ubiquitination assay, luciferase reporter assay, lentiviral LDHA overexpression rescue\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — conditional KO with defined fertility phenotype, ChIP, ubiquitination assay, and rescue; multiple orthogonal methods\",\n      \"pmids\": [\"36575252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXQ1 directly binds the circ_0000643 host gene promoter (ChIP assay) to increase circ_0000643 levels. circ_0000643 then sponges miR-153, which relieves repression of SLC7A11, reducing ferroptosis in breast cancer cells.\",\n      \"method\": \"ChIP assay for FOXQ1 at circ_0000643 host gene promoter, luciferase reporter assay, RIP assay for circ_0000643-miR-153 interaction, ferroptosis assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP establishing direct promoter binding; RIP confirming ceRNA interaction; single lab\",\n      \"pmids\": [\"37591453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXQ1 promotes LDHA transcription in pancreatic cancer cells to modulate aerobic glycolysis, thereby enhancing cell proliferation, tumor stemness, invasion, and metastasis. FOXQ1 silencing reduces LDHA expression and glycolysis.\",\n      \"method\": \"FOXQ1 overexpression and knockdown, ChIP assay for FOXQ1 at LDHA promoter, glycolysis measurement, in vivo xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP identifying direct LDHA promoter binding; single lab\",\n      \"pmids\": [\"37875474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KSHV immediate early protein ORF45 induces FOXQ1 expression in oral epithelial cells via the ORF45-RSK (ERK-p90RSK) signaling pathway. RTA also induces FOXQ1. FOXQ1 depletion reduces KSHV lytic protein accumulation and viral DNA, identifying FOXQ1 as a lytic cycle-sustaining host factor. FOXQ1 induction is associated with accumulation of activating histone acetylation marks at the FOXQ1 promoter.\",\n      \"method\": \"Transcriptome analysis of KSHV-infected HGEP cells, FOXQ1 knockdown in TIGK cells, screen of KSHV lytic proteins by ectopic expression, ORF45 RSK-activation mutant, ChIP for histone acetylation at FOXQ1 promoter\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function plus viral protein screen identifying upstream inducer mechanism; single lab\",\n      \"pmids\": [\"36815831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXQ1 transcriptionally activates CREB5, which suppresses NF-κB nuclear translocation of p65 to protect against sepsis-induced acute kidney injury. USP10 deubiquitinates FOXQ1, reducing its ubiquitination and promoting protein stability, and USP10 overexpression alleviates LPS-induced cell injury through FOXQ1.\",\n      \"method\": \"CLP mouse model, LPS-induced HK-2 cell model, luciferase reporter for CREB5, Co-IP for USP10-FOXQ1 interaction, in vivo ubiquitination assay, phosphorylation level assessment of p65\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay and reporter assay; in vivo and in vitro models; single lab\",\n      \"pmids\": [\"38960057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NAC1 interacts with BCL6 via NAC1's C-terminal BEN domain, and the NAC1-BCL6 complex binds the FOXQ1 promoter to activate FOXQ1 transcription. NAC1 also attenuates BCL6 auto-downregulation in ovarian cancer.\",\n      \"method\": \"Co-IP of NAC1 and BCL6, ChIP of NAC1-BCL6 complex at FOXQ1 promoter, luciferase reporter assay, Cistrome database analysis\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP and reporter assay; single lab\",\n      \"pmids\": [\"32412910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The FGFR1-MEK-ERK2 signaling pathway upregulates FOXQ1 gene expression through c-FOS binding to the FOXQ1 promoter. ERK2 (but not ERK1) is specifically required; ERK2 knockout suppresses FGFR1-stimulated FOXQ1 expression, and ectopic FOXQ1 rescues FGFR1-stimulated cell growth in ERK2-KO cells.\",\n      \"method\": \"MEK/ERK inhibitors, ERK1 and ERK2 CRISPR knockout, ChIP for c-FOS at FOXQ1 promoter, FOXQ1 rescue experiment, xenograft tumor growth\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP plus genetic epistasis (ERK1/ERK2 KO) and rescue; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"36778115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HNRNPA2B1 binds m6A-modified FOXQ1 mRNA and enhances its stability, increasing FOXQ1 protein expression. Silencing HNRNPA2B1 reduces FOXQ1 protein levels and suppresses OSCC malignant phenotypes.\",\n      \"method\": \"m6A site prediction, RIP/Co-IP for HNRNPA2B1-FOXQ1 mRNA interaction, mRNA stability assay, HNRNPA2B1 knockdown and overexpression, xenograft model\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirming direct RNA-protein binding with functional consequences; single lab\",\n      \"pmids\": [\"38265150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXQ1 expression is maintained by SIRT4-mediated metabolic control via the FOXQ1-SIRT4-GDH axis. FOXQ1 maintains SIRT4 expression; SIRT4 suppresses GDH via ADP-ribosylation. During senescence, FOXQ1 and SIRT4 decrease, causing increased GDH activity that produces α-KG, leading to H3K9me3 erasure at IL-6/IL-8 promoters and driving SASP.\",\n      \"method\": \"GDH activity assay in aged mice and senescent fibroblasts, FOXQ1/SIRT4 expression manipulation, ChIP for H3K9me3 at IL-6/IL-8 promoters, GDH pharmacological inhibition, α-KG metabolite measurement\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple gain/loss-of-function experiments with epigenetic readout; single lab\",\n      \"pmids\": [\"37516739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP1 stabilizes FOXQ1 protein by inhibiting its ubiquitination via the E3 ubiquitin ligase CHIP (STUB1), thereby protecting FOXQ1 from proteolytic degradation. Stabilized FOXQ1 activates LAMB3 transcription (ChIP-seq and luciferase assay), activating the WNT/β-catenin pathway to promote ovarian cancer progression.\",\n      \"method\": \"Co-IP of PARP1 and FOXQ1, mass spectrometry, in vivo ubiquitination assay, ChIP-seq, luciferase assay for LAMB3 promoter, PARP inhibitor experiments, xenograft and clinical samples\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP/MS, ubiquitination assay, ChIP-seq, reporter assay, in vivo drug treatment; multiple orthogonal methods in single study\",\n      \"pmids\": [\"38297082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JNK1 directly phosphorylates FOXQ1 at serine 248 in HCC cells in response to sorafenib. Phosphorylated FOXQ1 gains high affinity for the ETHE1 promoter and activates ETHE1 transcription. ETHE1 reduces intracellular lipid peroxidation and iron levels, thereby suppressing sorafenib-induced ferroptosis. This JNK1-FOXQ1(pS248)-ETHE1 axis mediates sorafenib resistance.\",\n      \"method\": \"In vitro kinase assay (JNK1 phosphorylating FOXQ1-S248), site-directed mutagenesis of S248, ChIP for FOXQ1 at ETHE1 promoter, flow cytometry for lipid peroxidation/iron, functional ferroptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus ChIP; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"38839744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"p53 is a negative transcriptional regulator of FOXQ1. p53 binds close to the FOXQ1 transcription start site and suppresses FOXQ1 expression. Pharmacological p53 activation (nutlin-3 or doxorubicin) reduces FOXQ1 mRNA and protein in cancer cells with wild-type p53; p53 mutations are associated with elevated FOXQ1 expression in human cancers.\",\n      \"method\": \"CRISPR-Cas9-based genomic locus proteomics to identify p53 as FOXQ1 regulator, ChIP-qPCR for p53 at FOXQ1 promoter, luciferase reporter assay, p53 gain/loss-of-function, nutlin-3 and doxorubicin pharmacological treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — CRISPR genomic locus proteomics plus ChIP plus reporter assay plus gain/loss-of-function plus pharmacological validation; multiple orthogonal methods\",\n      \"pmids\": [\"38432629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXQ1 regulates brain endothelial cell mitochondrial function through two direct mechanisms: (1) regulation of calcium signaling via huntingtin-associated protein (HAP1)-mediated ER-mitochondria calcium transfer, and (2) regulation of mitochondrial cristae integrity via ADCK1-dependent cristae organization. Endothelial-specific Foxq1 conditional knockout causes disrupted cristae morphology, reduced oxygen consumption, and impaired ATP production.\",\n      \"method\": \"Endothelial-specific conditional Foxq1 knockout, comparative transcriptomics, mitochondrial function assays (oxygen consumption, ATP production), electron microscopy for cristae, calcium imaging, identification of HAP1 and ADCK1 as direct targets\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — conditional knockout with defined organelle phenotype plus mechanistic target identification; multiple methods; single lab\",\n      \"pmids\": [\"40884816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Foxq1 alleviates postoperative cognitive dysfunction by activating the cannabinoid receptor CB2R, with oleamide as a mediator. Foxq1 overexpression (AAV) or oleamide administration improve cognitive performance and reduce hippocampal neuroinflammation; these effects are blocked by CB2R antagonist AM630.\",\n      \"method\": \"AAV-mediated hippocampal Foxq1 overexpression, oleamide administration, CB2R antagonist (AM630) rescue experiment, behavioral tests, inflammatory cytokine measurement, transcriptomic/metabolomic analysis\",\n      \"journal\": \"Brain pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with CB2R antagonist and genetic gain-of-function; single lab\",\n      \"pmids\": [\"39046224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Foxq1 promotes alveolar epithelial cell death in acute lung injury through Tle1-mediated inhibition of the NF-κB/Bcl2/Bax signaling pathway. Foxq1 knockdown promotes cell survival while overexpression has the opposite effect, with Tle1 identified as a mediating partner.\",\n      \"method\": \"LPS-induced ALI mouse model, Foxq1 knockdown and overexpression in MLE-12 cells, western blot for NF-κB/Bcl2/Bax, Tle1 functional assays\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss/gain-of-function with defined pathway readout; single lab\",\n      \"pmids\": [\"38574238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"p300 acetylates FOXQ1 at Lys190, enabling recognition and binding by BRD4. The resulting FOXQ1-p300-BRD4-RNA Pol II complex binds super-enhancer regions of target oncogenes, and acetylation at Lys190 directly enhances FOXQ1 binding affinity to super-enhancers, driving CRC proliferation and metastasis.\",\n      \"method\": \"ChIP-seq for FOXQ1 and BRD4 at super-enhancers, Co-IP of FOXQ1 complex, acetylation site mapping (Lys190), site-directed mutagenesis, luciferase reporter assay, in vitro and in vivo functional assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP-seq plus Co-IP plus site-specific mutagenesis identifying acetylation-dependent complex; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"40624346\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FOXQ1 is a forkhead transcription factor that drives epithelial-mesenchymal transition and metastasis by directly binding target gene promoters (E-cadherin/CDH1, TWIST1, Sox12, EGFR, LDHA, NDUFS1/NDUFV1, SIRT1, NRXN3) and recruiting transcriptional coactivators including the MLL/KMT2 histone methyltransferase complex via a direct interaction between its forkhead domain and RbBP5; its transcriptional output is context-dependent—acting as an oncogene in carcinomas (where it activates CDH2/N-cadherin in concert with nuclear β-catenin over TLE) but as a tumor suppressor in melanoma (where the lower β-catenin/TLE ratio causes CDH2 repression); FOXQ1 protein stability is post-translationally regulated by USP10-mediated deubiquitination, STUB1-mediated K63-linked polyubiquitination, PARP1-mediated protection from CHIP-dependent degradation, and JNK1-mediated phosphorylation at Ser248; upstream, FOXQ1 is transcriptionally induced by canonical Wnt signaling, TGF-β1, FGFR1-MEK-ERK2-c-FOS, and KSHV lytic factors, and is repressed by p53 and FOXF2/NCoR1/HDAC3; in metabolic contexts FOXQ1 regulates hepatic gluconeogenesis by blocking FOXO1, Sertoli cell lactate production via LDHA, and brain endothelial mitochondrial function via HAP1 and ADCK1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FOXQ1 is a forkhead/winged-helix transcription factor that acts as a sequence-specific, context-dependent regulator of cell differentiation, epithelial-mesenchymal transition (EMT), and metabolism by binding forkhead consensus elements in target gene promoters and recruiting chromatin-modifying coactivators [#2, #7, #34]. Its developmental and physiological roles were established in mice, where loss-of-function disrupts hair medulla differentiation (downstream of HOXC13) and abrogates secretagogue-stimulated gastric acid secretion [#0, #4, #5]. In carcinomas FOXQ1 functions as an oncogene driving EMT, invasion, and metastasis, repressing the epithelial adhesion gene CDH1/E-cadherin while activating pro-metastatic programs through direct promoter binding of TWIST1, Sox12, and EGFR [#7, #10, #13, #33]. Mechanistically, FOXQ1 initiates EMT transcription by recruiting the MLL/KMT2 histone methyltransferase complex via a direct interaction between its forkhead domain and the core subunit RbBP5, driving H3K4me3 deposition at EMT gene promoters [#34], and acetylation of FOXQ1 at Lys190 by p300 enables BRD4 recognition and assembly of a super-enhancer-bound FOXQ1-p300-BRD4-RNA Pol II complex [#53]. FOXQ1 transcriptional output is gated by the nuclear β-catenin/TLE ratio, which switches it between an oncogenic CDH2/N-cadherin activator in carcinomas and a tumor-suppressive CDH2 repressor in melanoma, where it instead promotes differentiation by directly activating MITF [#23, #26, #36]. Beyond cancer, FOXQ1 controls metabolism: it blocks FOXO1 to limit hepatic gluconeogenesis, transactivates LDHA to drive lactate production in Sertoli cells and glycolysis in tumor cells, regulates electron transport chain Complex I subunits NDUFS1/NDUFV1, and governs brain endothelial mitochondrial function via HAP1 and ADCK1 [#19, #31, #32, #40, #50]. FOXQ1 abundance is set transcriptionally by inducers including canonical Wnt signaling, TGF-β1, FGFR1-MEK-ERK2-c-FOS, and KSHV lytic factors and by repressors p53 and FOXF2/NCoR1/HDAC3, and post-translationally by USP10 deubiquitination, STUB1-mediated K63 polyubiquitination, PARP1-mediated protection from CHIP degradation, and JNK1 phosphorylation at Ser248, alongside mRNA stabilization by HuR and HNRNPA2B1 [#7, #12, #28, #29, #38, #42, #44, #47, #48, #49].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that FOXQ1 is a functionally required winged-helix transcription factor in vivo, answering whether the gene has a non-redundant developmental role.\",\n      \"evidence\": \"Genetic mapping of satin mice with an intragenic deletion and an ENU missense mutation in the DNA-binding domain producing identical hair medulla differentiation defects\",\n      \"pmids\": [\"11309849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify direct transcriptional targets in hair follicle\", \"Mechanism of medulla cell differentiation downstream not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the molecular basis of FOXQ1 DNA recognition, showing its winged-helix domain adopts DNA-bound conformations distinct from a close relative.\",\n      \"evidence\": \"Heteronuclear NMR structure of the HFH-1 DNA-binding domain free and DNA-bound, compared with Genesis\",\n      \"pmids\": [\"11876636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length structure or cofactor-bound complex\", \"Does not address activation versus repression determinants\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed FOXQ1 in a defined differentiation hierarchy as a direct HOXC13 target, explaining its developmental regulation.\",\n      \"evidence\": \"ChIP, reporter assays, and genetic epistasis in Hoxc13-transgenic and satin mice\",\n      \"pmids\": [\"16835220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FOXQ1 targets in medulla program not enumerated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated a distinct physiological role in gastric acid secretion, broadening FOXQ1 function beyond hair.\",\n      \"evidence\": \"Foxq1 knockout mice with acid secretion assays and ultrastructural analysis of parietal cells\",\n      \"pmids\": [\"18544931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets controlling tubulovesicle-membrane fusion unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified FOXQ1 as a driver of EMT and metastasis through direct CDH1/E-cadherin repression, establishing its oncogenic transcriptional program; independently replicated across two labs.\",\n      \"evidence\": \"ChIP/promoter binding at the CDH1 E-box, RNAi and ectopic expression, in vivo lung metastasis, TGF-β1 induction\",\n      \"pmids\": [\"21285253\", \"21346143\", \"20717954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coactivator/corepressor machinery not yet defined\", \"Mechanism of E-box repression not structurally resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded the FOXQ1 oncogenic target repertoire and positioned it within Wnt signaling, showing it both responds to and propagates pro-metastatic transcription.\",\n      \"evidence\": \"ChIP/reporter assays defining direct binding to TWIST1, NRXN3, and Wnt-responsive elements in the FOXQ1 promoter across CRC and glioma models\",\n      \"pmids\": [\"23723077\", \"23383267\", \"23555880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FOXQ1 acts as activator or repressor at a given promoter context-dependently not resolved here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Built out tumor-promoting axes and a TGF-β1/FOXQ1 feedback loop, linking FOXQ1 to stemness and chemoresistance.\",\n      \"evidence\": \"ChIP/site-directed mutagenesis (Sox12), PDGFR epistasis, and TGF-β1 promoter ChIP with functional EMT assays\",\n      \"pmids\": [\"25704764\", \"25502837\", \"25287361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect activation of some targets (PDGFRs) not fully separated\", \"TGF-β1 target claim rests on a single ChIP method\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected FOXQ1 to β-catenin nuclear translocation and to senescence/inflammation control via SIRT1, broadening its signaling and homeostatic roles.\",\n      \"evidence\": \"β-catenin fractionation/immunofluorescence with TGF-β1 stimulation; ChIP at SIRT1 promoter with cytokine and senescence readouts\",\n      \"pmids\": [\"25955104\", \"28726780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct FOXQ1-β-catenin binding assay in the CRC crosstalk study\", \"Whether SIRT1 axis operates in cancer as in fibroblasts not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a metabolic, non-cancer role for hepatic FOXQ1 in gluconeogenesis through a protein-protein interaction with FOXO1.\",\n      \"evidence\": \"Co-IP of FOXQ1-FOXO1, primary hepatocyte and in vivo gain/loss-of-function with glucose tolerance tests\",\n      \"pmids\": [\"27421728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FOXQ1-FOXO1 interaction unknown\", \"Whether FOXQ1 displaces FOXO1 directly at all gluconeogenic promoters not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed lineage-specific functional reversal, establishing that the nuclear β-catenin/TLE ratio switches FOXQ1 between CDH2 activator (carcinoma oncogene) and repressor (melanoma suppressor).\",\n      \"evidence\": \"Reciprocal Co-IP of FOXQ1 with β-catenin and TLE, β-catenin/TLE manipulation, in vivo metastasis models\",\n      \"pmids\": [\"28930679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative threshold of the β-catenin/TLE ratio not defined\", \"How TLE binding mechanistically converts activation to repression not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed FOXQ1 directly drives melanocyte differentiation by activating MITF via cAMP/CREB1, consistent with its tumor-suppressive role in melanoma.\",\n      \"evidence\": \"ChIP/reporter at MITF, cAMP/CREB1 activation, BRAFV600E models, in vivo pigmentation\",\n      \"pmids\": [\"29463842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of MITF activation with EMT repression in same lineage not fully detailed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified an upstream repressive mechanism: FOXF2 recruits NCoR1/HDAC3 to the FOXQ1 promoter, defining transcriptional control of FOXQ1 levels.\",\n      \"evidence\": \"ChIP showing NCoR1/HDAC3 recruitment, reporter assays, gain/loss-of-function in basal-like breast cancer\",\n      \"pmids\": [\"30807702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FOXF2-FOXQ1 mutual repression operates outside breast cancer untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established post-transcriptional control of FOXQ1 by RNA-binding proteins and added a Wnt-promoting role in osteogenesis via ANXA2.\",\n      \"evidence\": \"RIP showing HuR binding/stabilizing FOXQ1 mRNA with KH-3 disruption; Co-IP/MS identifying ANXA2 with β-catenin functional rescue; NAC1-BCL6 complex ChIP at FOXQ1 promoter\",\n      \"pmids\": [\"32332873\", \"32943107\", \"32412910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"m6A/sequence determinants of HuR binding not mapped here\", \"ANXA2-FOXQ1 mechanism of β-catenin activation indirect\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined FOXQ1 as a direct transcriptional regulator of cellular metabolism, controlling oxidative phosphorylation and lactate production through direct promoter binding.\",\n      \"evidence\": \"ChIP at NDUFS1/NDUFV1 with Complex I and Seahorse assays; ChIP at Ldha in Foxq1-knockout Sertoli cells with lactate rescue and fertility phenotyping; direct EGFR promoter binding driving vasculogenic mimicry\",\n      \"pmids\": [\"34939230\", \"34091745\", \"33875643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether metabolic versus EMT target selection is co-regulated unknown\", \"Tissue-specific cofactor requirements for metabolic targets undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the central coactivator mechanism: FOXQ1 recruits the MLL/KMT2 complex via a direct forkhead-domain–RbBP5 interaction to deposit H3K4me3 and initiate EMT, and acts as a differential Wnt target activator resembling TCF7L1.\",\n      \"evidence\": \"Co-IP with domain-mapping mutagenesis, H3K4me3 ChIP-seq, pharmacologic KMT2 inhibition, in vivo progression; RNA-seq/ChIP comparing cofactor recruitment with TCF7L1; shared DDR2 effector with SNAI1; STUB1 K63-ubiquitination of FOXQ1; SIRT1/β-catenin radioresistance axis\",\n      \"pmids\": [\"36319643\", \"36124643\", \"36713812\", \"36575252\", \"35183223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the FOXQ1-RbBP5/MLL complex not solved\", \"How acetylation/phosphorylation states feed into MLL recruitment unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped a multi-layered regulatory network setting FOXQ1 levels and activity—upstream kinase, viral, and tumor-suppressor inputs plus mRNA stabilization—and linked FOXQ1 to ferroptosis and metabolic-epigenetic aging axes.\",\n      \"evidence\": \"ChIP for c-FOS at FOXQ1 (FGFR1-MEK-ERK2); ORF45-RSK induction in KSHV; HNRNPA2B1 m6A-dependent mRNA stabilization; SIRT4-GDH-α-KG/H3K9me3 SASP axis; LDHA-driven glycolysis; circ_0000643/miR-153/SLC7A11 ferroptosis suppression; USP10 deubiquitination stabilizing FOXQ1; NDRG1/stellate-cell feedback\",\n      \"pmids\": [\"36778115\", \"36815831\", \"38265150\", \"37516739\", \"37875474\", \"37591453\", \"38960057\", \"29248714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy and crosstalk among the many input pathways not integrated\", \"Several axes (ferroptosis, SASP) rest on single-lab data\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined post-translational and transcriptional control nodes governing FOXQ1 stability and target specificity, and extended its role to brain endothelial mitochondrial function and CNS protection.\",\n      \"evidence\": \"PARP1 Co-IP/MS and ubiquitination assays protecting FOXQ1 from CHIP; JNK1 in vitro kinase assay phosphorylating Ser248 to redirect FOXQ1 to ETHE1 (ferroptosis/sorafenib resistance); p53 CRISPR genomic-locus proteomics and ChIP repressing FOXQ1; endothelial conditional knockout defining HAP1/ADCK1 mitochondrial targets; CB2R/oleamide cognitive role; Tle1-NF-κB lung injury axis\",\n      \"pmids\": [\"38297082\", \"38839744\", \"38432629\", \"40884816\", \"39046224\", \"38574238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation at Ser248 reprograms genome-wide binding not mapped\", \"Interplay between PARP1, STUB1, USP10, and CHIP in setting FOXQ1 half-life not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed acetylation-dependent assembly of a super-enhancer-bound FOXQ1 complex, providing a chromatin mechanism for its potent oncogenic output.\",\n      \"evidence\": \"p300 acetylation of FOXQ1 Lys190, BRD4 recognition, FOXQ1-p300-BRD4-RNA Pol II ChIP-seq at super-enhancers with site-directed mutagenesis\",\n      \"pmids\": [\"40624346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between Lys190 acetylation and MLL/RbBP5 recruitment unresolved\", \"Genome-wide super-enhancer target set not exhaustively defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the combinatorial post-translational code (acetylation, phosphorylation, ubiquitination) and cofactor ratio (β-catenin/TLE, MLL, p300/BRD4) are integrated to select activating versus repressive target programs in a given cell type.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking FOXQ1 modification state to genome-wide target choice\", \"No high-resolution structure of FOXQ1 in cofactor complexes\", \"Context determinants of oncogene-versus-suppressor switch not generalized beyond melanoma/carcinoma\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 7, 10, 13, 23, 26, 31, 32, 33, 36, 53]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 2, 7, 31, 32, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 23, 34, 53]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 10, 13, 31, 32, 33, 34, 53]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 16, 23, 30, 36]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [19, 31, 32, 40, 50]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [34, 46, 53]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 4, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 23, 47, 48]}\n    ],\n    \"complexes\": [\"MLL/KMT2 histone methyltransferase complex\", \"FOXQ1-p300-BRD4-RNA Pol II super-enhancer complex\"],\n    \"partners\": [\"RbBP5\", \"CTNNB1\", \"TLE\", \"FOXO1\", \"STUB1\", \"USP10\", \"PARP1\", \"p300\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}