{"gene":"FOXK1","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2019,"finding":"FOXK1 and FOXK2 induce aerobic glycolysis by transcriptionally upregulating glycolytic enzymes (hexokinase-2, phosphofructokinase, pyruvate kinase, lactate dehydrogenase) and suppressing mitochondrial pyruvate oxidation by increasing pyruvate dehydrogenase kinases 1 and 4 and suppressing pyruvate dehydrogenase phosphatase 1, leading to increased phosphorylation of the E1α subunit of the pyruvate dehydrogenase complex and thus diverting pyruvate to lactate.","method":"In vitro transcriptional assays, in vivo mouse models, primary human cell studies, gene expression analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal in vitro and in vivo experiments, mechanistic pathway fully defined, replicated across human and mouse systems","pmids":["30700909"],"is_preprint":false},{"year":2018,"finding":"mTORC1 promotes nuclear localization and activity of FOXK1 by suppressing GSK3-dependent phosphorylation of FOXK1; when mTORC1 is suppressed, GSK3 phosphorylates FOXK1, inducing 14-3-3 binding, reduced DNA binding, and nuclear exclusion. This pathway regulates glycolytic and anabolic gene expression including HIF-1α.","method":"Phosphoproteomics, co-immunoprecipitation, nuclear fractionation, DNA binding assays, genetic manipulation of mTORC1/GSK3","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic dissection with multiple orthogonal methods including phosphoproteomics and functional rescue, strong mechanistic detail","pmids":["29861159"],"is_preprint":false},{"year":2019,"finding":"Following insulin stimulation, FOXK1 and FOXK2 translocate from cytoplasm to nucleus in a reciprocal manner to FoxO1; this translocation is dependent on the Akt-mTOR pathway, while cytoplasmic localization in basal state is dependent on GSK3. Knockdown of FoxK1/K2 in liver cells upregulates apoptosis genes and downregulates cell cycle and lipid metabolism genes, leading to decreased proliferation and altered mitochondrial fatty acid metabolism.","method":"Subcellular fractionation, live cell imaging, siRNA knockdown, RNA-seq, pathway inhibitor experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including direct localization, genetic knockdown, and transcriptomic analysis with clear functional readouts","pmids":["30952843"],"is_preprint":false},{"year":2017,"finding":"mTORC1 activation induces PP2A-mediated dephosphorylation of FOXK1, resulting in transactivation of the CCL2 gene in a manner independent of NF-κB; this promotes tumor-associated macrophage recruitment. Identified by phosphoproteomics as a downstream target of mTORC1.","method":"Multiple phosphoproteomics approaches, luciferase reporter assay, chromatin immunoprecipitation, in vivo tumor models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple phosphoproteomics approaches plus ChIP and in vivo validation, mechanistic pathway defined","pmids":["29186685"],"is_preprint":false},{"year":2002,"finding":"Foxk1 is essential for myogenic progenitor cell cycle progression; Foxk1-null mice show G0/G1 arrest and upregulation of the CDK inhibitor p21CIP. Combinatorial knockout of Foxk1 and p21CIP rescues growth deficit, muscle regeneration, and cell cycle progression, placing p21CIP downstream of Foxk1.","method":"Genetic epistasis (double-mutant mice), cell cycle analysis, molecular analysis of Foxk1-/- myogenic progenitor cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with double KO rescue, multiple cellular phenotypic readouts","pmids":["12446708"],"is_preprint":false},{"year":2012,"finding":"FOXK1 promotes myogenic progenitor cell proliferation and represses differentiation by physically interacting with and repressing the transcriptional activity of Foxo4 and Mef2. Knockdown of Foxk1 in C2C12 myoblasts causes cell cycle arrest, and overexpression retards muscle differentiation.","method":"Co-immunoprecipitation, transcriptional reporter assays, knockdown and overexpression experiments, cell cycle analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, transcriptional assays, and loss/gain of function with defined cellular phenotypes","pmids":["22956541"],"is_preprint":false},{"year":2007,"finding":"FOXK1 interacts with SRF in human cells and acts as a transcriptional repressor of SRF target genes SM alpha-actin and PPGB; FOXK1 binding to these promoters requires SRF occupancy.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, promoter binding studies","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction shown, ChIP confirms promoter occupancy, functional reporter assays demonstrate repression","pmids":["17670796"],"is_preprint":false},{"year":2010,"finding":"FOXK1 interacts with the LIM-only protein Fhl2; Fhl2 dose-dependently promotes FOXK1-mediated transcriptional repression of Foxo4 activity in myogenic progenitor cells. Fhl2 knockdown causes cell cycle arrest and mice lacking Fhl2 show perturbed skeletal muscle regeneration.","method":"Yeast two-hybrid screen, transcriptional reporter assays, knockdown experiments, in vivo mouse regeneration model","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — yeast two-hybrid with functional follow-up and in vivo validation, single lab","pmids":["20013826"],"is_preprint":false},{"year":2012,"finding":"Foxk1 interacts with Sin3 transcriptional corepressor through the Foxk1 N-terminal (1-40) region (Sin3 interacting domain) and the PAH2 domain of Sin3, as determined by yeast two-hybrid and GST pulldown. Sin3a/b knockdown results in cell cycle arrest and upregulation of cell cycle inhibitor genes in myogenic progenitor cells.","method":"Yeast two-hybrid screen, GST pulldown assay, siRNA knockdown, cell cycle analysis","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — GST pulldown maps domain interaction, functional consequence shown by knockdown","pmids":["22476904"],"is_preprint":false},{"year":2007,"finding":"Sox15 directly binds an evolutionarily conserved site in the Foxk1 promoter and recruits Fhl3 to transcriptionally coactivate Foxk1 gene expression in myogenic progenitor cells. Sox15 knockdown reduces Foxk1 expression and perturbs cell cycle kinetics; Sox15 mutant mice show perturbed skeletal muscle regeneration.","method":"Transgenic reporter assay, chromatin immunoprecipitation, knockdown experiments, Sox15 mutant mouse analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — ChIP confirms binding, transgenic in vivo reporter, genetic mouse model, multiple orthogonal methods","pmids":["17363903"],"is_preprint":false},{"year":2010,"finding":"Adenovirus E1A C-terminus and beta-HPV E6 proteins interact with FOXK1/K2 through a conserved Ser/Thr-containing motif; E1A mutants deficient in FOXK1/K2 interaction show enhanced cell proliferation and oncogenic transformation, demonstrating that FOXK1/K2 interaction suppresses E1A-mediated transformation.","method":"Tandem affinity purification, mass spectrometry, co-immunoprecipitation, cell transformation assays, mutational analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — mass spectrometry identification, mutagenesis, functional transformation assays, mechanistic motif defined","pmids":["20053746"],"is_preprint":false},{"year":2020,"finding":"FOXK1 is a core component of the PR-DUB complex (with BAP1, HCFC1, OGT, and ASXL proteins) and is required for BAP1-mediated H2AK119ub1 deubiquitination and recruitment to chromatin for gene activation. FOXK1/2 facilitate BAP1 genome-wide binding and gene activation independently of PRC2.","method":"ChIP-seq, CRISPR knockout, mass spectrometry complex analysis, genome-wide transcriptomic analysis","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 1-2 — genome-wide ChIP-seq combined with CRISPR KO and transcriptomic analysis, complex biochemistry established","pmids":["32747411"],"is_preprint":false},{"year":2020,"finding":"ASXL1 interacts with FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes; C-terminally truncated mutant ASXL1 (leukemia-associated) loses the ability to interact with FOXK1/K2, and specific deletion of the mutant allele restores BAP1-ASXL1-FOXK1/K2 target gene expression involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling.","method":"Co-immunoprecipitation, mass spectrometry, allele-specific deletion, gene expression analysis","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, mass spectrometry, allele-specific genetic manipulation with defined transcriptional outcomes","pmids":["32683582"],"is_preprint":false},{"year":2020,"finding":"FOXK1 associates with 53BP1 and regulates 53BP1-dependent DNA repair choice between NHEJ and HR. The FOXK1-53BP1 interaction is enhanced upon DNA damage during S phase in an ATM/CHK2-dependent manner, reducing 53BP1 association with RIF1 and PTIP. FOXK1 overexpression diminishes 53BP1 foci and leads to resistance to PARPi in BRCA1-deficient cells.","method":"Co-immunoprecipitation, live cell imaging, siRNA depletion, PARPi sensitivity assays, telomere fusion assays, DNA damage response analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple functional assays with specific phenotypic readouts, ATM/CHK2 dependence established","pmids":["32783940"],"is_preprint":false},{"year":2022,"finding":"HDAC3 interacts with FOXK1 and co-localizes with it at the promoters of STAT1 and STAT2; HDAC3 is required to protect FOXK1 from lysosomal system-mediated degradation. Loss of either HDAC3 or FOXK1 in macrophages decreases STAT1/STAT2 expression and impairs antiviral immunity.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, CRISPR knockout, gene expression analysis, viral challenge assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP confirms co-occupancy at promoters, genetic KO with defined functional phenotype","pmids":["35081346"],"is_preprint":false},{"year":2016,"finding":"FOXK1 physically interacts with FHL2 in colorectal cancer cells; siRNA-mediated repression of FHL2 in FOXK1-overexpressing cells reverses EMT, proliferative, and metastatic phenotypes in vitro and in vivo.","method":"Co-immunoprecipitation, shRNA-mediated knockdown, in vitro migration/invasion assays, in vivo xenograft","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP with functional rescue experiments, single lab","pmids":["27892920"],"is_preprint":false},{"year":2018,"finding":"FOXK1 physically interacts with and stabilizes vimentin in gastric cancer cells; co-expression of FOXK1 and vimentin enhances EMT, and siRNA repression of vimentin in FOXK1-overexpressing cells reverses the EMT-like phenotype.","method":"Co-immunoprecipitation, siRNA knockdown, in vitro EMT assays, in vivo xenograft","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP with functional validation, single lab","pmids":["30483822"],"is_preprint":false},{"year":2016,"finding":"c-jun directly binds to and activates the human FOXK1 gene promoter, as demonstrated by promoter reporter and chromatin immunoprecipitation assays. siRNA-mediated repression of c-jun in FOXK1-overexpressing cells reverses EMT and proliferative/metastatic phenotypes.","method":"Luciferase reporter assay, chromatin immunoprecipitation, siRNA knockdown, in vivo orthotopic implantation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP confirms direct binding, luciferase validates promoter activity, functional rescue performed","pmids":["27882939"],"is_preprint":false},{"year":2018,"finding":"Snail directly binds to and activates the human FOXK1 gene promoter; FOXK1 in turn directly activates transcription of Cyr61 (confirmed by luciferase assays), mediating Snail/FOXK1/Cyr61-driven EMT and metastasis in colorectal cancer.","method":"Chromatin immunoprecipitation, luciferase reporter assay, in vitro migration/invasion assays, in vivo metastasis model","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP confirms Snail binding to FOXK1 promoter and FOXK1 binding to Cyr61 promoter, functional cascade validated","pmids":["29794466"],"is_preprint":false},{"year":2018,"finding":"FOXK1 directly binds and activates the human CCDC43 gene promoter (confirmed by chromatin immunoprecipitation and promoter assays), and CCDC43 is required for FOXK1-mediated EMT and metastasis in colorectal cancer.","method":"Chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown, flow cytometry, invasion assays","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP and reporter confirm direct transcriptional target, functional consequence demonstrated","pmids":["30562730"],"is_preprint":false},{"year":2017,"finding":"FOXK1 physically interacts with RUFY3 in colorectal cancer cells; siRNA-mediated repression of FOXK1 in RUFY3-overexpressing cells reverses EMT and metastatic phenotypes in vitro and in vivo.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, in vivo orthotopic implantation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP with functional rescue, single lab","pmids":["28623323"],"is_preprint":false},{"year":2018,"finding":"FOXK1 promotes glioblastoma cell proliferation via the S-phase and activates transcription of Snail, as demonstrated by luciferase reporter assay and chromatin immunoprecipitation, thereby promoting EMT and metastasis.","method":"Luciferase reporter assay, chromatin immunoprecipitation, loss/gain of function experiments","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 3 — ChIP and luciferase confirm Snail as direct FOXK1 target, single lab","pmids":["29456714"],"is_preprint":false},{"year":2017,"finding":"FOXK1 facilitates cell cycle progression in ovarian cancer by transcriptionally regulating p21 expression, as shown by ChIP and luciferase reporter assay. FOXK1 knockdown leads to reduced proliferation and cell cycle arrest.","method":"Chromatin immunoprecipitation, luciferase reporter assay, cell cycle analysis, CCK-8 and colony formation assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 — ChIP and luciferase confirm FOXK1 binding to p21 promoter, functional consequence shown","pmids":["29050292"],"is_preprint":false},{"year":2018,"finding":"FOXK1 suppression in liver cancer cells reduces hexokinase 2 (HK2) expression, decreases glucose consumption and lactate production, and inhibits the Akt/mTOR pathway, demonstrating that FOXK1 promotes aerobic glycolysis through HK2 and Akt/mTOR.","method":"siRNA knockdown, qRT-PCR, western blot, glucose consumption and lactate production assays, MTT/CCK-8","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, indirect mechanistic link, no direct transcriptional binding assay for HK2 in this study","pmids":["30312701"],"is_preprint":false},{"year":2020,"finding":"FOXK1 interacts with the transcription factor DLC1 in the nucleus of melanoma cells (identified by mass spectrometry); DLC1-FOXK1 cooperatively activates MMP9 expression through FOXK1-mediated promoter occupancy, promoting invasion and metastasis independent of DLC1's RhoGAP activity.","method":"Mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation, RNA-sequencing, loss/gain of function assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — mass spectrometry identification confirmed by Co-IP and ChIP, RNA-seq profiling, mechanistic link to MMP9 defined","pmids":["32214200"],"is_preprint":false},{"year":2018,"finding":"Nuclear-cytoplasmic shuttling of PP2A regulatory subunit B56 is required for mTORC1-dependent dephosphorylation of FOXK1; B56 acts as the mediating component between cytoplasmic mTORC1 and nuclear FOXK1.","method":"Nuclear-cytoplasmic transport inhibition, phosphorylation assays, genetic manipulation of B56","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — identifies specific PP2A subunit mediating mTORC1-FOXK1 signal, single lab","pmids":["29845697"],"is_preprint":false},{"year":2023,"finding":"FOXK1 regulates cardiogenesis by repressing the Wnt/β-catenin signaling pathway to promote cardiac progenitor cell differentiation; Foxk1 KO embryoid bodies show impaired chromatin accessibility at cardiac regulatory regions and reduced expression of the cardiac molecular program.","method":"CRISPR KO, flow cytometry, bulk RNA-seq, ATAC-seq, ChIP-qPCR, cardiac beating and contractility assays","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genome-wide approaches with genetic KO, clear mechanistic conclusion about Wnt pathway repression","pmids":["37036809"],"is_preprint":false},{"year":2025,"finding":"Foxk1 and Foxk2 drive cardiomyocyte cell cycle progression by directly activating CCNB1 and CDK1 expression, forming the CCNB1/CDK1 complex that facilitates G2/M transition. They also promote cardiomyocyte proliferation by upregulating HIF1α, which enhances glycolysis and the pentose phosphate pathway.","method":"Cardiomyocyte-specific KO, AAV9-mediated overexpression, ChIP, RNA-seq, in vivo myocardial infarction model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — cardiomyocyte-specific KO and AAV rescue, ChIP confirms direct gene targets, multiple in vivo and in vitro readouts","pmids":["40128196"],"is_preprint":false},{"year":2024,"finding":"FOXK1 binds to promoter regions of glycolytic enzyme genes (identified by CUT&Tag analysis) and promotes aerobic glycolysis in osteoblasts; conditional KO of Foxk1 in preosteoblasts reduces aerobic glycolysis and decreases bone mass and mechanical strength, an effect rescued by Foxk1 overexpression but blocked by glycolysis inhibition.","method":"CUT&Tag, conditional KO mouse model, glycolysis assays, bone microstructure analysis, AAV-mediated overexpression","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — CUT&Tag genome-wide binding plus in vivo conditional KO and rescue with glycolysis inhibitor, mechanistic link established","pmids":["39232134"],"is_preprint":false},{"year":2020,"finding":"Aurora-A kinase phosphorylates the transcription factor SOX8 at Ser327, which in turn promotes FOXK1 expression, thereby regulating genes related to cell senescence (hTERT, P16) and glycolysis (LDHA, HK2) to drive chemoresistance in ovarian cancer.","method":"Immunoprecipitation, mass spectrometry, FRET-FLIM, luciferase reporter assay, ChIP, organoid models","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — mass spectrometry and FRET-FLIM confirm direct protein interactions, ChIP validates downstream targets, organoid models","pmids":["32550913"],"is_preprint":false},{"year":2023,"finding":"FOXK1 directly binds to promoter regions of CDC25A and CDK4 and activates their transcription in esophageal squamous cell carcinoma cells (confirmed by ChIP and luciferase assay); knockdown of either CDC25A or CDK4 reverses FOXK1 overexpression-mediated biological effects including radioresistance.","method":"Chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown, radiation sensitivity assays, cell cycle analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP and luciferase confirm direct transcriptional activation, functional rescue performed, single lab","pmids":["37173384"],"is_preprint":false},{"year":2025,"finding":"FOXK1, but not FOXK2, is specifically modified by O-GlcNAcylation; this modification is modulated during the cell cycle and peaks at G1/S. O-GlcNAcylation of FOXK1 is required for its ability to recruit BAP1 to E2F target gene regulatory regions, maintain active chromatin (reduced H2AK119ub, maintained H3K4me1), and promote E2F pathway gene expression, cell proliferation, and cellular transformation.","method":"O-GlcNAc mutagenesis, ChIP-seq, cell proliferation/transformation assays, chromatin modification analysis, tumor growth assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of modification site, ChIP-seq genome-wide, multiple orthogonal functional assays, peer-reviewed","pmids":["40593803"],"is_preprint":false},{"year":2024,"finding":"FOXK1 O-GlcNAcylation is identified; FOXK1 O-GlcNAc-defective mutants show reduced BAP1 recruitment to E2F target genes and increased H2AK119ub levels, confirming that O-GlcNAcylation co-opts the tumor suppressor BAP1 to promote transcription of E2F target genes and oncogenesis.","method":"O-GlcNAc mutagenesis, ChIP-seq, gene expression analysis, tumor growth assays","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic mutagenesis and ChIP-seq; published in peer-reviewed form (PMID 40593803), preprint version here","pmids":["38463952"],"is_preprint":true},{"year":2024,"finding":"FOXK1 recruits the REST/CoREST transcriptional corepression complex to transcriptionally inhibit apoptotic pathway genes in ER+ breast cancer cells, as determined by ChIP-seq and mass spectrometry; this prevents apoptosis and promotes ER+ breast tumor progression.","method":"Silver staining mass spectrometry, Co-IP, ChIP-seq, TUNEL assay, xenograft models","journal":"Animal models and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — mass spectrometry and ChIP-seq with functional in vivo validation, single lab","pmids":["38238876"],"is_preprint":false},{"year":2024,"finding":"FOXK1 recruits multiple corepressor complexes (NCoR/SMRT, SIN3A, NuRD, REST/CoREST); the FOXK1/NCoR/SIN3A complex transcriptionally represses circadian clock genes CLOCK, PER2, and CRY2, promoting breast cancer proliferation. Insulin resistance increases OGT expression, which causes FOXK1 nuclear translocation and increased expression.","method":"ChIP-seq, co-immunoprecipitation, luciferase reporter assay, chromatin modification analysis, inhibitor studies","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq and Co-IP establish complex components and target genes, mechanistic link to circadian disruption defined","pmids":["39094826"],"is_preprint":false},{"year":2023,"finding":"FoxK1 binding sites are found at promoters and enhancers of over 4000 genes in liver cells; insulin enhances FoxK1 binding at ~75% of target genes. ChIP-seq comparison shows that FoxK1 may act as a transcription factor partner for some reported roles of the insulin receptor in gene regulation.","method":"ChIP-seq, siRNA knockdown, gene expression analysis","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide ChIP-seq in liver cells with insulin stimulation, functional validation by knockdown","pmids":["37852413"],"is_preprint":false},{"year":2025,"finding":"USP28 interacts with FOXK1 and mediates its deubiquitination and stabilization; FOXK1 promotes cell proliferation and radioresistance in lung cancer through activation of the Hippo signaling pathway.","method":"In vitro ubiquitination assay, co-immunoprecipitation, RNA-seq, xenograft model, siRNA knockdown","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vitro ubiquitination assay confirms deubiquitination, RNA-seq identifies Hippo pathway, single lab","pmids":["39983825"],"is_preprint":false},{"year":2024,"finding":"KSHV ORF45 binds FOXK1 via a conserved serine/threonine linear motif that interacts with the FOXK1 FHA domain; a single threonine point mutation in ORF45 abolishes this interaction. FoxK1 and FoxK2 directly bind to promoters of several late viral genes, and ORF45 augments their promoter binding and transcriptional activity to promote late viral gene expression.","method":"Co-immunoprecipitation, mutagenesis, ChIP, lytic reactivation assays, depletion experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — mutagenesis of interaction motif, ChIP confirms promoter occupancy, depletion shows functional requirement, two papers corroborate","pmids":["39494902","39287387"],"is_preprint":false},{"year":2023,"finding":"Foxk1 directly binds to the Pparγ2 promoter and stimulates its transcriptional activity, promoting adipocyte differentiation from progenitor cells. Adipogenic stimulation induces nuclear translocation of Foxk1 in an mTOR- and PI3-kinase-dependent manner.","method":"ChIP, luciferase reporter assay, loss/gain of function in BMSCs and cell lines, pathway inhibitor studies","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP and luciferase confirm direct binding to Pparγ2 promoter, pathway inhibition validates nuclear translocation mechanism","pmids":["37889840"],"is_preprint":false},{"year":2022,"finding":"A natural antisense RNA, Foxk1-AS, is transcribed from the opposite strand of Foxk1 DNA and targets Foxk1 to suppress its expression; overexpression of Foxk1-AS inhibits Foxk1 and promotes myoblast differentiation and muscle regeneration by rescuing Mef2c activity.","method":"Lentivirus/AAV overexpression and knockdown, qRT-PCR, western blotting, immunofluorescence, in vivo muscle regeneration model","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 3 — antisense RNA mechanism demonstrated with functional readouts in cells and in vivo, single lab","pmids":["35642035"],"is_preprint":false},{"year":2025,"finding":"O-GlcNAcylation of FOXK1 at Thr573 (identified by proteomic profiling) inhibits ubiquitination-mediated degradation of PES1; increased PES1 promotes AKR1C18 activity to reduce progesterone levels, thereby disrupting oocyte maturation and early embryonic development.","method":"Proteomic O-GlcNAcylation profiling, co-immunoprecipitation combined with LC-MS/MS, site-specific mutagenesis, in vivo mouse exposure model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — site-specific modification identified by proteomics and confirmed by Co-IP/LC-MS/MS, functional consequence in vivo; single lab","pmids":["41388345"],"is_preprint":false}],"current_model":"FOXK1 is a forkhead/winged helix transcription factor that integrates nutrient and growth factor signaling (via the mTORC1-GSK3-Akt axis controlling its nuclear-cytoplasmic shuttling) to regulate aerobic glycolysis, cell cycle progression, and metabolic gene expression; it functions within the PR-DUB complex (with BAP1, ASXL proteins, and OGT) to remove H2AK119ub1 and activate target genes, is modified by O-GlcNAcylation which promotes BAP1 recruitment and E2F pathway activation, directly binds promoters of glycolytic enzymes, p21, CDC25A, CDK4, and other targets, interacts with SRF, Foxo4, Mef2, Sin3, FHL2, 53BP1, and REST/CoREST to modulate transcriptional programs governing muscle progenitor cell proliferation/differentiation, cardiogenesis, metabolism, DNA repair, and antiviral immunity, while its nuclear translocation, stability, and activity are regulated by GSK3 phosphorylation, 14-3-3 binding, PP2A (B56) dephosphorylation, USP28 deubiquitination, and HDAC3-mediated protection from lysosomal degradation."},"narrative":{"teleology":[{"year":2002,"claim":"The first genetic loss-of-function study established that Foxk1 is essential for myogenic progenitor cell cycle progression by repressing the CDK inhibitor p21, resolving whether Foxk1 had a functional role beyond DNA binding.","evidence":"Foxk1-null mice and Foxk1/p21 double-knockout epistasis analysis in myogenic progenitor cells","pmids":["12446708"],"confidence":"High","gaps":["Mechanism of p21 repression (direct versus indirect) not established","Upstream signals controlling Foxk1 activity unknown"]},{"year":2007,"claim":"Identification of SRF as a FOXK1 interaction partner and demonstration that FOXK1 represses SRF target genes established FOXK1 as a transcriptional corepressor that requires partner-factor occupancy for promoter access.","evidence":"Co-immunoprecipitation, ChIP, and luciferase reporter assays on SM α-actin and PPGB promoters","pmids":["17670796"],"confidence":"High","gaps":["Whether SRF-FOXK1 interaction is direct or bridged by other factors","Genome-wide scope of SRF-dependent FOXK1 targets unknown"]},{"year":2010,"claim":"Discovery that FHL2 cooperates with FOXK1 to repress Foxo4 transcriptional activity linked a LIM-domain cofactor to the FOXK1-mediated control of myogenic progenitor proliferation versus differentiation balance, while viral oncoprotein studies showed that adenovirus E1A and HPV E6 target the FOXK1 FHA domain, indicating evolutionary exploitation of this interaction surface.","evidence":"Yeast two-hybrid and reporter assays for FHL2; TAP-MS, mutagenesis, and transformation assays for E1A/E6","pmids":["20013826","20053746"],"confidence":"High","gaps":["Structural basis of FOXK1 FHA domain recognition not resolved","Physiological relevance of viral–FOXK1 interaction in infection unclear"]},{"year":2012,"claim":"Mapping of the Sin3 interaction domain to the FOXK1 N-terminus and demonstration that FOXK1 represses both Foxo4 and Mef2 defined the corepressor recruitment mechanism through which FOXK1 maintains myoblast proliferation and blocks premature differentiation.","evidence":"GST pulldown, co-IP, knockdown/overexpression with cell cycle and differentiation readouts in C2C12 myoblasts","pmids":["22476904","22956541"],"confidence":"Medium","gaps":["Whether Sin3a and Sin3b are redundant in FOXK1-dependent repression","Genome-wide targets of FOXK1–Sin3 not defined"]},{"year":2017,"claim":"Phosphoproteomic identification of FOXK1 as an mTORC1-regulated substrate and dissection of the GSK3-dependent phosphorylation/14-3-3 binding/nuclear exclusion circuit revealed how nutrient and growth factor signals control FOXK1 nuclear localization and transcriptional activity.","evidence":"Phosphoproteomics, nuclear fractionation, DNA binding assays, genetic manipulation of mTORC1 and GSK3","pmids":["29186685","29861159"],"confidence":"High","gaps":["Specific GSK3 phosphorylation sites on FOXK1 not fully mapped","Whether mTORC1 acts through additional intermediaries beyond PP2A"]},{"year":2018,"claim":"The PP2A regulatory subunit B56 was identified as the specific mediator shuttling the mTORC1 signal to nuclear FOXK1, and insulin-stimulated reciprocal shuttling of FOXK1 (nuclear) versus FoxO1 (cytoplasmic) was demonstrated, establishing the Akt-mTOR-GSK3-PP2A(B56) axis as the complete signaling cascade.","evidence":"Nuclear-cytoplasmic transport inhibition, B56 genetic manipulation, live-cell imaging, RNA-seq in liver cells","pmids":["29845697","30952843"],"confidence":"High","gaps":["Whether additional phosphatases contribute in specific tissues","Quantitative kinetics of FOXK1 shuttling not established"]},{"year":2019,"claim":"A landmark metabolic study demonstrated that FOXK1 directly activates transcription of glycolytic enzymes (HK2, PFK, PKM2, LDHA) and pyruvate dehydrogenase kinases while repressing pyruvate dehydrogenase phosphatase, establishing FOXK1 as a master transcriptional driver of aerobic glycolysis (Warburg effect).","evidence":"Transcriptional assays, in vivo mouse models, primary human cell studies with comprehensive metabolic and gene expression analysis","pmids":["30700909"],"confidence":"High","gaps":["Whether FOXK1 and FOXK2 are fully redundant in glycolytic gene activation","Direct versus indirect targets not genome-wide resolved at this stage"]},{"year":2020,"claim":"FOXK1 was established as a core chromatin-targeting subunit of the PR-DUB complex (BAP1/ASXL1/HCFC1/OGT) required for genome-wide BAP1 recruitment, H2AK119ub1 removal, and gene activation, while leukemia-associated ASXL1 truncation mutations were shown to disrupt the ASXL1–FOXK1 interaction and target gene expression.","evidence":"ChIP-seq, CRISPR knockout, mass spectrometry, allele-specific deletion, transcriptomic analysis","pmids":["32747411","32683582"],"confidence":"High","gaps":["Whether FOXK1 and FOXK2 share all PR-DUB target sites","How FOXK1 is itself recruited to specific genomic loci"]},{"year":2020,"claim":"Discovery that FOXK1 interacts with 53BP1 in an ATM/CHK2-dependent manner during S phase and shifts DNA repair from NHEJ toward HR by displacing RIF1/PTIP extended FOXK1 function beyond transcription into DNA damage response regulation.","evidence":"Co-IP, live-cell imaging, siRNA, PARPi sensitivity and telomere fusion assays","pmids":["32783940"],"confidence":"High","gaps":["Structural basis of FOXK1–53BP1 interaction unresolved","Whether this function is FHA-domain dependent","Relevance in non-cancer primary cells not tested"]},{"year":2022,"claim":"HDAC3 was shown to protect FOXK1 from lysosomal degradation and co-occupy STAT1/STAT2 promoters with FOXK1, establishing a FOXK1-dependent transcriptional mechanism for innate antiviral immunity in macrophages.","evidence":"Co-IP, ChIP, CRISPR KO macrophages, viral challenge assays","pmids":["35081346"],"confidence":"High","gaps":["Mechanism of HDAC3-mediated protection from lysosomal degradation unknown","Whether FOXK1 acts as activator or derepressor at STAT1/2 loci"]},{"year":2023,"claim":"FOXK1 was shown to repress Wnt/β-catenin signaling during cardiogenesis and to directly activate cardiac cell cycle genes CCNB1/CDK1, establishing its role as a key regulator of cardiac progenitor differentiation and cardiomyocyte proliferation.","evidence":"CRISPR KO embryoid bodies, ATAC-seq, RNA-seq, cardiomyocyte-specific KO, AAV9 rescue, in vivo MI model","pmids":["37036809","40128196"],"confidence":"High","gaps":["Whether FOXK1 directly binds Wnt pathway gene promoters","Redundancy with FOXK2 in cardiomyocytes not addressed"]},{"year":2024,"claim":"CUT&Tag and conditional KO in osteoblasts confirmed that FOXK1 directly occupies glycolytic gene promoters in bone, and that its metabolic function is required for bone formation, generalizing the FOXK1–glycolysis axis to mesenchymal lineages.","evidence":"CUT&Tag, conditional Foxk1 KO in preosteoblasts, glycolysis assays, bone microstructure analysis, AAV rescue with glycolysis inhibitor","pmids":["39232134"],"confidence":"High","gaps":["Whether HIF1α mediates FOXK1's glycolytic effects in bone as in heart","Contribution of FOXK2 in osteoblasts untested"]},{"year":2024,"claim":"KSHV ORF45 was found to bind the FOXK1 FHA domain through a phosphothreonine-containing linear motif, augmenting FOXK1 promoter binding and late viral gene transcription — revealing that viruses exploit FOXK1's FHA domain to hijack host transcriptional machinery.","evidence":"Co-IP, point mutagenesis of ORF45 threonine, ChIP, lytic reactivation assays","pmids":["39494902","39287387"],"confidence":"High","gaps":["Whether cellular FHA-binding partners use the same motif","Crystal structure of FOXK1 FHA–ligand complex not available"]},{"year":2025,"claim":"O-GlcNAcylation of FOXK1 was shown to be required for BAP1 recruitment to E2F target gene regulatory regions and for maintaining active chromatin; this modification is cell-cycle regulated, peaking at G1/S, and is essential for FOXK1-driven cellular transformation.","evidence":"O-GlcNAc site mutagenesis, ChIP-seq, chromatin modification analysis, proliferation/transformation assays, tumor growth assays","pmids":["40593803"],"confidence":"High","gaps":["Identity and number of specific O-GlcNAcylated residues governing BAP1 interaction not fully mapped","Whether O-GlcNAcylation affects FOXK1 interactions beyond BAP1"]},{"year":2025,"claim":"USP28-mediated deubiquitination was identified as a mechanism stabilizing FOXK1 protein levels, adding another layer of post-translational regulation distinct from HDAC3-mediated lysosomal protection.","evidence":"In vitro ubiquitination assay, co-IP, RNA-seq, xenograft model","pmids":["39983825"],"confidence":"Medium","gaps":["E3 ligase responsible for FOXK1 ubiquitination not identified","Relationship between USP28 and HDAC3 protective mechanisms unclear","Single-lab finding awaits independent confirmation"]},{"year":null,"claim":"Key unresolved questions include: (1) the structural basis for FOXK1's context-dependent switching between transcriptional activation and repression; (2) the full catalog of O-GlcNAcylation sites and how each modifies specific protein interactions; (3) whether FOXK1 and FOXK2 are truly redundant at most genomic loci; and (4) how FOXK1's transcriptional, chromatin-remodeling, and DNA repair functions are coordinated in a cell-cycle-dependent manner.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structural model of FOXK1 in complex with chromatin or cofactors","Genome-wide functional separation of FOXK1 vs FOXK2 not systematically performed","Integration of metabolic, cell cycle, and DNA repair functions into a unified regulatory model lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,11,22,27,28,30,35,37,38]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,6,11,22,26,27,30,33,34,38]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,11,24,31,35]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,6,11,22,26,27,30,33,34,38]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,5,22,27,30,31]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,23,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3,25,26]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[11,31,32]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5,26,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14]}],"complexes":["PR-DUB (BAP1/ASXL1/HCFC1/OGT)","NCoR/SMRT corepressor complex","SIN3 corepressor complex","REST/CoREST corepressor complex"],"partners":["BAP1","ASXL1","SRF","FHL2","TP53BP1","SIN3A","HDAC3","OGT"],"other_free_text":[]},"mechanistic_narrative":"FOXK1 is a forkhead/winged-helix transcription factor that integrates nutrient and growth factor signaling with transcriptional programs governing aerobic glycolysis, cell cycle progression, differentiation, and DNA repair. Its nuclear-cytoplasmic shuttling is controlled by the mTORC1–GSK3 axis: mTORC1 activation promotes PP2A(B56)-mediated dephosphorylation of FOXK1, enabling nuclear entry and DNA binding, whereas GSK3-dependent phosphorylation triggers 14-3-3 binding and cytoplasmic sequestration [PMID:29861159, PMID:29845697, PMID:30952843]. Within the nucleus, FOXK1 functions as a core chromatin-targeting subunit of the PR-DUB complex (BAP1, ASXL1/2, OGT, HCFC1), where O-GlcNAcylation of FOXK1 is required for BAP1 recruitment to E2F target gene regulatory regions to remove H2AK119ub1 and activate transcription [PMID:32747411, PMID:40593803, PMID:32683582]. FOXK1 directly binds promoters of glycolytic enzymes (HK2, PFK, PKM, LDHA), pyruvate dehydrogenase kinases, cell cycle regulators (p21, CDC25A, CDK4, CCNB1/CDK1), and lineage-specific genes (Pparγ2, STAT1/2), and recruits corepressor complexes (Sin3, NCoR/SMRT, REST/CoREST) or coactivators in a context-dependent manner to control myogenic progenitor proliferation, cardiomyocyte cell cycle re-entry, osteoblast metabolism, adipogenesis, and antiviral innate immunity [PMID:30700909, PMID:12446708, PMID:40128196, PMID:39232134, PMID:35081346, PMID:37889840, PMID:39094826]."},"prefetch_data":{"uniprot":{"accession":"P85037","full_name":"Forkhead box protein K1","aliases":["Myocyte nuclear factor","MNF"],"length_aa":733,"mass_kda":75.5,"function":"Transcriptional regulator involved in different processes such as glucose metabolism, aerobic glycolysis, muscle cell differentiation and autophagy (By similarity). Recognizes and binds the forkhead DNA sequence motif (5'-GTAAACA-3') and can both act as a transcription activator or repressor, depending on the context (PubMed:17670796). Together with FOXK2, acts as a key regulator of metabolic reprogramming towards aerobic glycolysis, a process in which glucose is converted to lactate in the presence of oxygen (By similarity). Acts by promoting expression of enzymes for glycolysis (such as hexokinase-2 (HK2), phosphofructokinase, pyruvate kinase (PKLR) and lactate dehydrogenase), while suppressing further oxidation of pyruvate in the mitochondria by up-regulating pyruvate dehydrogenase kinases PDK1 and PDK4 (By similarity). Probably plays a role in gluconeogenesis during overnight fasting, when lactate from white adipose tissue and muscle is the main substrate (By similarity). Involved in mTORC1-mediated metabolic reprogramming: in response to mTORC1 signaling, translocates into the nucleus and regulates the expression of genes associated with glycolysis and downstream anabolic pathways, such as HIF1A, thereby regulating glucose metabolism (By similarity). Together with FOXK2, acts as a negative regulator of autophagy in skeletal muscle: in response to starvation, enters the nucleus, binds the promoters of autophagy genes and represses their expression, preventing proteolysis of skeletal muscle proteins (By similarity). Acts as a transcriptional regulator of the myogenic progenitor cell population in skeletal muscle (By similarity). Binds to the upstream enhancer region (CCAC box) of myoglobin (MB) gene, regulating the myogenic progenitor cell population (By similarity). Promotes muscle progenitor cell proliferation by repressing the transcriptional activity of FOXO4, thereby inhibiting myogenic differentiation (By similarity). Involved in remodeling processes of adult muscles that occur in response to physiological stimuli (By similarity). Required to correct temporal orchestration of molecular and cellular events necessary for muscle repair (By similarity). Represses myogenic differentiation by inhibiting MEFC activity (By similarity). Positively regulates Wnt/beta-catenin signaling by translocating DVL into the nucleus (PubMed:25805136). Reduces virus replication, probably by binding the interferon stimulated response element (ISRE) to promote antiviral gene expression (PubMed:25852164). Accessory component of the polycomb repressive deubiquitinase (PR-DUB) complex; recruits the PR-DUB complex to specific FOXK1-bound genes (PubMed:24634419, PubMed:30664650). Acts as an indirect positive regulator of ferroptosis following phosphorylation by isoform Beta-II of PRKCB by promoting expression and subsequent secretion of LGALS13 (PubMed:40246981)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P85037/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FOXK1","classification":"Not Classified","n_dependent_lines":227,"n_total_lines":1208,"dependency_fraction":0.1879139072847682},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PPM1G","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FOXK1","total_profiled":1310},"omim":[{"mim_id":"616302","title":"FORKHEAD BOX K1; FOXK1","url":"https://www.omim.org/entry/616302"},{"mim_id":"147685","title":"FORKHEAD BOX K2; FOXK2","url":"https://www.omim.org/entry/147685"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FOXK1"},"hgnc":{"alias_symbol":["IMAGE:5164497"],"prev_symbol":[]},"alphafold":{"accession":"P85037","domains":[{"cath_id":"2.60.200.20","chopping":"104-204","consensus_level":"high","plddt":91.6686,"start":104,"end":204},{"cath_id":"1.10.10.10","chopping":"311-395","consensus_level":"high","plddt":93.3774,"start":311,"end":395}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P85037","model_url":"https://alphafold.ebi.ac.uk/files/AF-P85037-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P85037-F1-predicted_aligned_error_v6.png","plddt_mean":56.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FOXK1","jax_strain_url":"https://www.jax.org/strain/search?query=FOXK1"},"sequence":{"accession":"P85037","fasta_url":"https://rest.uniprot.org/uniprotkb/P85037.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P85037/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P85037"}},"corpus_meta":[{"pmid":"30700909","id":"PMC_30700909","title":"FOXK1 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diverting pyruvate to lactate.\",\n      \"method\": \"In vitro transcriptional assays, in vivo mouse models, primary human cell studies, gene expression analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal in vitro and in vivo experiments, mechanistic pathway fully defined, replicated across human and mouse systems\",\n      \"pmids\": [\"30700909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"mTORC1 promotes nuclear localization and activity of FOXK1 by suppressing GSK3-dependent phosphorylation of FOXK1; when mTORC1 is suppressed, GSK3 phosphorylates FOXK1, inducing 14-3-3 binding, reduced DNA binding, and nuclear exclusion. This pathway regulates glycolytic and anabolic gene expression including HIF-1α.\",\n      \"method\": \"Phosphoproteomics, co-immunoprecipitation, nuclear fractionation, DNA binding assays, genetic manipulation of mTORC1/GSK3\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic dissection with multiple orthogonal methods including phosphoproteomics and functional rescue, strong mechanistic detail\",\n      \"pmids\": [\"29861159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Following insulin stimulation, FOXK1 and FOXK2 translocate from cytoplasm to nucleus in a reciprocal manner to FoxO1; this translocation is dependent on the Akt-mTOR pathway, while cytoplasmic localization in basal state is dependent on GSK3. Knockdown of FoxK1/K2 in liver cells upregulates apoptosis genes and downregulates cell cycle and lipid metabolism genes, leading to decreased proliferation and altered mitochondrial fatty acid metabolism.\",\n      \"method\": \"Subcellular fractionation, live cell imaging, siRNA knockdown, RNA-seq, pathway inhibitor experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including direct localization, genetic knockdown, and transcriptomic analysis with clear functional readouts\",\n      \"pmids\": [\"30952843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"mTORC1 activation induces PP2A-mediated dephosphorylation of FOXK1, resulting in transactivation of the CCL2 gene in a manner independent of NF-κB; this promotes tumor-associated macrophage recruitment. Identified by phosphoproteomics as a downstream target of mTORC1.\",\n      \"method\": \"Multiple phosphoproteomics approaches, luciferase reporter assay, chromatin immunoprecipitation, in vivo tumor models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple phosphoproteomics approaches plus ChIP and in vivo validation, mechanistic pathway defined\",\n      \"pmids\": [\"29186685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Foxk1 is essential for myogenic progenitor cell cycle progression; Foxk1-null mice show G0/G1 arrest and upregulation of the CDK inhibitor p21CIP. Combinatorial knockout of Foxk1 and p21CIP rescues growth deficit, muscle regeneration, and cell cycle progression, placing p21CIP downstream of Foxk1.\",\n      \"method\": \"Genetic epistasis (double-mutant mice), cell cycle analysis, molecular analysis of Foxk1-/- myogenic progenitor cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with double KO rescue, multiple cellular phenotypic readouts\",\n      \"pmids\": [\"12446708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FOXK1 promotes myogenic progenitor cell proliferation and represses differentiation by physically interacting with and repressing the transcriptional activity of Foxo4 and Mef2. Knockdown of Foxk1 in C2C12 myoblasts causes cell cycle arrest, and overexpression retards muscle differentiation.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, knockdown and overexpression experiments, cell cycle analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, transcriptional assays, and loss/gain of function with defined cellular phenotypes\",\n      \"pmids\": [\"22956541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FOXK1 interacts with SRF in human cells and acts as a transcriptional repressor of SRF target genes SM alpha-actin and PPGB; FOXK1 binding to these promoters requires SRF occupancy.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, promoter binding studies\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction shown, ChIP confirms promoter occupancy, functional reporter assays demonstrate repression\",\n      \"pmids\": [\"17670796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FOXK1 interacts with the LIM-only protein Fhl2; Fhl2 dose-dependently promotes FOXK1-mediated transcriptional repression of Foxo4 activity in myogenic progenitor cells. Fhl2 knockdown causes cell cycle arrest and mice lacking Fhl2 show perturbed skeletal muscle regeneration.\",\n      \"method\": \"Yeast two-hybrid screen, transcriptional reporter assays, knockdown experiments, in vivo mouse regeneration model\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid with functional follow-up and in vivo validation, single lab\",\n      \"pmids\": [\"20013826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Foxk1 interacts with Sin3 transcriptional corepressor through the Foxk1 N-terminal (1-40) region (Sin3 interacting domain) and the PAH2 domain of Sin3, as determined by yeast two-hybrid and GST pulldown. Sin3a/b knockdown results in cell cycle arrest and upregulation of cell cycle inhibitor genes in myogenic progenitor cells.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown assay, siRNA knockdown, cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — GST pulldown maps domain interaction, functional consequence shown by knockdown\",\n      \"pmids\": [\"22476904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Sox15 directly binds an evolutionarily conserved site in the Foxk1 promoter and recruits Fhl3 to transcriptionally coactivate Foxk1 gene expression in myogenic progenitor cells. Sox15 knockdown reduces Foxk1 expression and perturbs cell cycle kinetics; Sox15 mutant mice show perturbed skeletal muscle regeneration.\",\n      \"method\": \"Transgenic reporter assay, chromatin immunoprecipitation, knockdown experiments, Sox15 mutant mouse analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms binding, transgenic in vivo reporter, genetic mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"17363903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Adenovirus E1A C-terminus and beta-HPV E6 proteins interact with FOXK1/K2 through a conserved Ser/Thr-containing motif; E1A mutants deficient in FOXK1/K2 interaction show enhanced cell proliferation and oncogenic transformation, demonstrating that FOXK1/K2 interaction suppresses E1A-mediated transformation.\",\n      \"method\": \"Tandem affinity purification, mass spectrometry, co-immunoprecipitation, cell transformation assays, mutational analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mass spectrometry identification, mutagenesis, functional transformation assays, mechanistic motif defined\",\n      \"pmids\": [\"20053746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOXK1 is a core component of the PR-DUB complex (with BAP1, HCFC1, OGT, and ASXL proteins) and is required for BAP1-mediated H2AK119ub1 deubiquitination and recruitment to chromatin for gene activation. FOXK1/2 facilitate BAP1 genome-wide binding and gene activation independently of PRC2.\",\n      \"method\": \"ChIP-seq, CRISPR knockout, mass spectrometry complex analysis, genome-wide transcriptomic analysis\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide ChIP-seq combined with CRISPR KO and transcriptomic analysis, complex biochemistry established\",\n      \"pmids\": [\"32747411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ASXL1 interacts with FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes; C-terminally truncated mutant ASXL1 (leukemia-associated) loses the ability to interact with FOXK1/K2, and specific deletion of the mutant allele restores BAP1-ASXL1-FOXK1/K2 target gene expression involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, allele-specific deletion, gene expression analysis\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mass spectrometry, allele-specific genetic manipulation with defined transcriptional outcomes\",\n      \"pmids\": [\"32683582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOXK1 associates with 53BP1 and regulates 53BP1-dependent DNA repair choice between NHEJ and HR. The FOXK1-53BP1 interaction is enhanced upon DNA damage during S phase in an ATM/CHK2-dependent manner, reducing 53BP1 association with RIF1 and PTIP. FOXK1 overexpression diminishes 53BP1 foci and leads to resistance to PARPi in BRCA1-deficient cells.\",\n      \"method\": \"Co-immunoprecipitation, live cell imaging, siRNA depletion, PARPi sensitivity assays, telomere fusion assays, DNA damage response analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple functional assays with specific phenotypic readouts, ATM/CHK2 dependence established\",\n      \"pmids\": [\"32783940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC3 interacts with FOXK1 and co-localizes with it at the promoters of STAT1 and STAT2; HDAC3 is required to protect FOXK1 from lysosomal system-mediated degradation. Loss of either HDAC3 or FOXK1 in macrophages decreases STAT1/STAT2 expression and impairs antiviral immunity.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, CRISPR knockout, gene expression analysis, viral challenge assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP confirms co-occupancy at promoters, genetic KO with defined functional phenotype\",\n      \"pmids\": [\"35081346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FOXK1 physically interacts with FHL2 in colorectal cancer cells; siRNA-mediated repression of FHL2 in FOXK1-overexpressing cells reverses EMT, proliferative, and metastatic phenotypes in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, shRNA-mediated knockdown, in vitro migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional rescue experiments, single lab\",\n      \"pmids\": [\"27892920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXK1 physically interacts with and stabilizes vimentin in gastric cancer cells; co-expression of FOXK1 and vimentin enhances EMT, and siRNA repression of vimentin in FOXK1-overexpressing cells reverses the EMT-like phenotype.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, in vitro EMT assays, in vivo xenograft\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional validation, single lab\",\n      \"pmids\": [\"30483822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"c-jun directly binds to and activates the human FOXK1 gene promoter, as demonstrated by promoter reporter and chromatin immunoprecipitation assays. siRNA-mediated repression of c-jun in FOXK1-overexpressing cells reverses EMT and proliferative/metastatic phenotypes.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation, siRNA knockdown, in vivo orthotopic implantation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP confirms direct binding, luciferase validates promoter activity, functional rescue performed\",\n      \"pmids\": [\"27882939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Snail directly binds to and activates the human FOXK1 gene promoter; FOXK1 in turn directly activates transcription of Cyr61 (confirmed by luciferase assays), mediating Snail/FOXK1/Cyr61-driven EMT and metastasis in colorectal cancer.\",\n      \"method\": \"Chromatin immunoprecipitation, luciferase reporter assay, in vitro migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP confirms Snail binding to FOXK1 promoter and FOXK1 binding to Cyr61 promoter, functional cascade validated\",\n      \"pmids\": [\"29794466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXK1 directly binds and activates the human CCDC43 gene promoter (confirmed by chromatin immunoprecipitation and promoter assays), and CCDC43 is required for FOXK1-mediated EMT and metastasis in colorectal cancer.\",\n      \"method\": \"Chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown, flow cytometry, invasion assays\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and reporter confirm direct transcriptional target, functional consequence demonstrated\",\n      \"pmids\": [\"30562730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXK1 physically interacts with RUFY3 in colorectal cancer cells; siRNA-mediated repression of FOXK1 in RUFY3-overexpressing cells reverses EMT and metastatic phenotypes in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, in vivo orthotopic implantation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional rescue, single lab\",\n      \"pmids\": [\"28623323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXK1 promotes glioblastoma cell proliferation via the S-phase and activates transcription of Snail, as demonstrated by luciferase reporter assay and chromatin immunoprecipitation, thereby promoting EMT and metastasis.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation, loss/gain of function experiments\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — ChIP and luciferase confirm Snail as direct FOXK1 target, single lab\",\n      \"pmids\": [\"29456714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXK1 facilitates cell cycle progression in ovarian cancer by transcriptionally regulating p21 expression, as shown by ChIP and luciferase reporter assay. FOXK1 knockdown leads to reduced proliferation and cell cycle arrest.\",\n      \"method\": \"Chromatin immunoprecipitation, luciferase reporter assay, cell cycle analysis, CCK-8 and colony formation assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — ChIP and luciferase confirm FOXK1 binding to p21 promoter, functional consequence shown\",\n      \"pmids\": [\"29050292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXK1 suppression in liver cancer cells reduces hexokinase 2 (HK2) expression, decreases glucose consumption and lactate production, and inhibits the Akt/mTOR pathway, demonstrating that FOXK1 promotes aerobic glycolysis through HK2 and Akt/mTOR.\",\n      \"method\": \"siRNA knockdown, qRT-PCR, western blot, glucose consumption and lactate production assays, MTT/CCK-8\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, indirect mechanistic link, no direct transcriptional binding assay for HK2 in this study\",\n      \"pmids\": [\"30312701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FOXK1 interacts with the transcription factor DLC1 in the nucleus of melanoma cells (identified by mass spectrometry); DLC1-FOXK1 cooperatively activates MMP9 expression through FOXK1-mediated promoter occupancy, promoting invasion and metastasis independent of DLC1's RhoGAP activity.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation, RNA-sequencing, loss/gain of function assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mass spectrometry identification confirmed by Co-IP and ChIP, RNA-seq profiling, mechanistic link to MMP9 defined\",\n      \"pmids\": [\"32214200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nuclear-cytoplasmic shuttling of PP2A regulatory subunit B56 is required for mTORC1-dependent dephosphorylation of FOXK1; B56 acts as the mediating component between cytoplasmic mTORC1 and nuclear FOXK1.\",\n      \"method\": \"Nuclear-cytoplasmic transport inhibition, phosphorylation assays, genetic manipulation of B56\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — identifies specific PP2A subunit mediating mTORC1-FOXK1 signal, single lab\",\n      \"pmids\": [\"29845697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXK1 regulates cardiogenesis by repressing the Wnt/β-catenin signaling pathway to promote cardiac progenitor cell differentiation; Foxk1 KO embryoid bodies show impaired chromatin accessibility at cardiac regulatory regions and reduced expression of the cardiac molecular program.\",\n      \"method\": \"CRISPR KO, flow cytometry, bulk RNA-seq, ATAC-seq, ChIP-qPCR, cardiac beating and contractility assays\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genome-wide approaches with genetic KO, clear mechanistic conclusion about Wnt pathway repression\",\n      \"pmids\": [\"37036809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Foxk1 and Foxk2 drive cardiomyocyte cell cycle progression by directly activating CCNB1 and CDK1 expression, forming the CCNB1/CDK1 complex that facilitates G2/M transition. They also promote cardiomyocyte proliferation by upregulating HIF1α, which enhances glycolysis and the pentose phosphate pathway.\",\n      \"method\": \"Cardiomyocyte-specific KO, AAV9-mediated overexpression, ChIP, RNA-seq, in vivo myocardial infarction model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cardiomyocyte-specific KO and AAV rescue, ChIP confirms direct gene targets, multiple in vivo and in vitro readouts\",\n      \"pmids\": [\"40128196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK1 binds to promoter regions of glycolytic enzyme genes (identified by CUT&Tag analysis) and promotes aerobic glycolysis in osteoblasts; conditional KO of Foxk1 in preosteoblasts reduces aerobic glycolysis and decreases bone mass and mechanical strength, an effect rescued by Foxk1 overexpression but blocked by glycolysis inhibition.\",\n      \"method\": \"CUT&Tag, conditional KO mouse model, glycolysis assays, bone microstructure analysis, AAV-mediated overexpression\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CUT&Tag genome-wide binding plus in vivo conditional KO and rescue with glycolysis inhibitor, mechanistic link established\",\n      \"pmids\": [\"39232134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Aurora-A kinase phosphorylates the transcription factor SOX8 at Ser327, which in turn promotes FOXK1 expression, thereby regulating genes related to cell senescence (hTERT, P16) and glycolysis (LDHA, HK2) to drive chemoresistance in ovarian cancer.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, FRET-FLIM, luciferase reporter assay, ChIP, organoid models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mass spectrometry and FRET-FLIM confirm direct protein interactions, ChIP validates downstream targets, organoid models\",\n      \"pmids\": [\"32550913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXK1 directly binds to promoter regions of CDC25A and CDK4 and activates their transcription in esophageal squamous cell carcinoma cells (confirmed by ChIP and luciferase assay); knockdown of either CDC25A or CDK4 reverses FOXK1 overexpression-mediated biological effects including radioresistance.\",\n      \"method\": \"Chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown, radiation sensitivity assays, cell cycle analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and luciferase confirm direct transcriptional activation, functional rescue performed, single lab\",\n      \"pmids\": [\"37173384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOXK1, but not FOXK2, is specifically modified by O-GlcNAcylation; this modification is modulated during the cell cycle and peaks at G1/S. O-GlcNAcylation of FOXK1 is required for its ability to recruit BAP1 to E2F target gene regulatory regions, maintain active chromatin (reduced H2AK119ub, maintained H3K4me1), and promote E2F pathway gene expression, cell proliferation, and cellular transformation.\",\n      \"method\": \"O-GlcNAc mutagenesis, ChIP-seq, cell proliferation/transformation assays, chromatin modification analysis, tumor growth assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of modification site, ChIP-seq genome-wide, multiple orthogonal functional assays, peer-reviewed\",\n      \"pmids\": [\"40593803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK1 O-GlcNAcylation is identified; FOXK1 O-GlcNAc-defective mutants show reduced BAP1 recruitment to E2F target genes and increased H2AK119ub levels, confirming that O-GlcNAcylation co-opts the tumor suppressor BAP1 to promote transcription of E2F target genes and oncogenesis.\",\n      \"method\": \"O-GlcNAc mutagenesis, ChIP-seq, gene expression analysis, tumor growth assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic mutagenesis and ChIP-seq; published in peer-reviewed form (PMID 40593803), preprint version here\",\n      \"pmids\": [\"38463952\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK1 recruits the REST/CoREST transcriptional corepression complex to transcriptionally inhibit apoptotic pathway genes in ER+ breast cancer cells, as determined by ChIP-seq and mass spectrometry; this prevents apoptosis and promotes ER+ breast tumor progression.\",\n      \"method\": \"Silver staining mass spectrometry, Co-IP, ChIP-seq, TUNEL assay, xenograft models\",\n      \"journal\": \"Animal models and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mass spectrometry and ChIP-seq with functional in vivo validation, single lab\",\n      \"pmids\": [\"38238876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOXK1 recruits multiple corepressor complexes (NCoR/SMRT, SIN3A, NuRD, REST/CoREST); the FOXK1/NCoR/SIN3A complex transcriptionally represses circadian clock genes CLOCK, PER2, and CRY2, promoting breast cancer proliferation. Insulin resistance increases OGT expression, which causes FOXK1 nuclear translocation and increased expression.\",\n      \"method\": \"ChIP-seq, co-immunoprecipitation, luciferase reporter assay, chromatin modification analysis, inhibitor studies\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq and Co-IP establish complex components and target genes, mechanistic link to circadian disruption defined\",\n      \"pmids\": [\"39094826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FoxK1 binding sites are found at promoters and enhancers of over 4000 genes in liver cells; insulin enhances FoxK1 binding at ~75% of target genes. ChIP-seq comparison shows that FoxK1 may act as a transcription factor partner for some reported roles of the insulin receptor in gene regulation.\",\n      \"method\": \"ChIP-seq, siRNA knockdown, gene expression analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq in liver cells with insulin stimulation, functional validation by knockdown\",\n      \"pmids\": [\"37852413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP28 interacts with FOXK1 and mediates its deubiquitination and stabilization; FOXK1 promotes cell proliferation and radioresistance in lung cancer through activation of the Hippo signaling pathway.\",\n      \"method\": \"In vitro ubiquitination assay, co-immunoprecipitation, RNA-seq, xenograft model, siRNA knockdown\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vitro ubiquitination assay confirms deubiquitination, RNA-seq identifies Hippo pathway, single lab\",\n      \"pmids\": [\"39983825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KSHV ORF45 binds FOXK1 via a conserved serine/threonine linear motif that interacts with the FOXK1 FHA domain; a single threonine point mutation in ORF45 abolishes this interaction. FoxK1 and FoxK2 directly bind to promoters of several late viral genes, and ORF45 augments their promoter binding and transcriptional activity to promote late viral gene expression.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, ChIP, lytic reactivation assays, depletion experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of interaction motif, ChIP confirms promoter occupancy, depletion shows functional requirement, two papers corroborate\",\n      \"pmids\": [\"39494902\", \"39287387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Foxk1 directly binds to the Pparγ2 promoter and stimulates its transcriptional activity, promoting adipocyte differentiation from progenitor cells. Adipogenic stimulation induces nuclear translocation of Foxk1 in an mTOR- and PI3-kinase-dependent manner.\",\n      \"method\": \"ChIP, luciferase reporter assay, loss/gain of function in BMSCs and cell lines, pathway inhibitor studies\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and luciferase confirm direct binding to Pparγ2 promoter, pathway inhibition validates nuclear translocation mechanism\",\n      \"pmids\": [\"37889840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A natural antisense RNA, Foxk1-AS, is transcribed from the opposite strand of Foxk1 DNA and targets Foxk1 to suppress its expression; overexpression of Foxk1-AS inhibits Foxk1 and promotes myoblast differentiation and muscle regeneration by rescuing Mef2c activity.\",\n      \"method\": \"Lentivirus/AAV overexpression and knockdown, qRT-PCR, western blotting, immunofluorescence, in vivo muscle regeneration model\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — antisense RNA mechanism demonstrated with functional readouts in cells and in vivo, single lab\",\n      \"pmids\": [\"35642035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"O-GlcNAcylation of FOXK1 at Thr573 (identified by proteomic profiling) inhibits ubiquitination-mediated degradation of PES1; increased PES1 promotes AKR1C18 activity to reduce progesterone levels, thereby disrupting oocyte maturation and early embryonic development.\",\n      \"method\": \"Proteomic O-GlcNAcylation profiling, co-immunoprecipitation combined with LC-MS/MS, site-specific mutagenesis, in vivo mouse exposure model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific modification identified by proteomics and confirmed by Co-IP/LC-MS/MS, functional consequence in vivo; single lab\",\n      \"pmids\": [\"41388345\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FOXK1 is a forkhead/winged helix transcription factor that integrates nutrient and growth factor signaling (via the mTORC1-GSK3-Akt axis controlling its nuclear-cytoplasmic shuttling) to regulate aerobic glycolysis, cell cycle progression, and metabolic gene expression; it functions within the PR-DUB complex (with BAP1, ASXL proteins, and OGT) to remove H2AK119ub1 and activate target genes, is modified by O-GlcNAcylation which promotes BAP1 recruitment and E2F pathway activation, directly binds promoters of glycolytic enzymes, p21, CDC25A, CDK4, and other targets, interacts with SRF, Foxo4, Mef2, Sin3, FHL2, 53BP1, and REST/CoREST to modulate transcriptional programs governing muscle progenitor cell proliferation/differentiation, cardiogenesis, metabolism, DNA repair, and antiviral immunity, while its nuclear translocation, stability, and activity are regulated by GSK3 phosphorylation, 14-3-3 binding, PP2A (B56) dephosphorylation, USP28 deubiquitination, and HDAC3-mediated protection from lysosomal degradation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FOXK1 is a forkhead/winged-helix transcription factor that integrates nutrient and growth factor signaling with transcriptional programs governing aerobic glycolysis, cell cycle progression, differentiation, and DNA repair. Its nuclear-cytoplasmic shuttling is controlled by the mTORC1–GSK3 axis: mTORC1 activation promotes PP2A(B56)-mediated dephosphorylation of FOXK1, enabling nuclear entry and DNA binding, whereas GSK3-dependent phosphorylation triggers 14-3-3 binding and cytoplasmic sequestration [PMID:29861159, PMID:29845697, PMID:30952843]. Within the nucleus, FOXK1 functions as a core chromatin-targeting subunit of the PR-DUB complex (BAP1, ASXL1/2, OGT, HCFC1), where O-GlcNAcylation of FOXK1 is required for BAP1 recruitment to E2F target gene regulatory regions to remove H2AK119ub1 and activate transcription [PMID:32747411, PMID:40593803, PMID:32683582]. FOXK1 directly binds promoters of glycolytic enzymes (HK2, PFK, PKM, LDHA), pyruvate dehydrogenase kinases, cell cycle regulators (p21, CDC25A, CDK4, CCNB1/CDK1), and lineage-specific genes (Pparγ2, STAT1/2), and recruits corepressor complexes (Sin3, NCoR/SMRT, REST/CoREST) or coactivators in a context-dependent manner to control myogenic progenitor proliferation, cardiomyocyte cell cycle re-entry, osteoblast metabolism, adipogenesis, and antiviral innate immunity [PMID:30700909, PMID:12446708, PMID:40128196, PMID:39232134, PMID:35081346, PMID:37889840, PMID:39094826].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"The first genetic loss-of-function study established that Foxk1 is essential for myogenic progenitor cell cycle progression by repressing the CDK inhibitor p21, resolving whether Foxk1 had a functional role beyond DNA binding.\",\n      \"evidence\": \"Foxk1-null mice and Foxk1/p21 double-knockout epistasis analysis in myogenic progenitor cells\",\n      \"pmids\": [\"12446708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of p21 repression (direct versus indirect) not established\", \"Upstream signals controlling Foxk1 activity unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of SRF as a FOXK1 interaction partner and demonstration that FOXK1 represses SRF target genes established FOXK1 as a transcriptional corepressor that requires partner-factor occupancy for promoter access.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, and luciferase reporter assays on SM α-actin and PPGB promoters\",\n      \"pmids\": [\"17670796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SRF-FOXK1 interaction is direct or bridged by other factors\", \"Genome-wide scope of SRF-dependent FOXK1 targets unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that FHL2 cooperates with FOXK1 to repress Foxo4 transcriptional activity linked a LIM-domain cofactor to the FOXK1-mediated control of myogenic progenitor proliferation versus differentiation balance, while viral oncoprotein studies showed that adenovirus E1A and HPV E6 target the FOXK1 FHA domain, indicating evolutionary exploitation of this interaction surface.\",\n      \"evidence\": \"Yeast two-hybrid and reporter assays for FHL2; TAP-MS, mutagenesis, and transformation assays for E1A/E6\",\n      \"pmids\": [\"20013826\", \"20053746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FOXK1 FHA domain recognition not resolved\", \"Physiological relevance of viral–FOXK1 interaction in infection unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapping of the Sin3 interaction domain to the FOXK1 N-terminus and demonstration that FOXK1 represses both Foxo4 and Mef2 defined the corepressor recruitment mechanism through which FOXK1 maintains myoblast proliferation and blocks premature differentiation.\",\n      \"evidence\": \"GST pulldown, co-IP, knockdown/overexpression with cell cycle and differentiation readouts in C2C12 myoblasts\",\n      \"pmids\": [\"22476904\", \"22956541\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Sin3a and Sin3b are redundant in FOXK1-dependent repression\", \"Genome-wide targets of FOXK1–Sin3 not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Phosphoproteomic identification of FOXK1 as an mTORC1-regulated substrate and dissection of the GSK3-dependent phosphorylation/14-3-3 binding/nuclear exclusion circuit revealed how nutrient and growth factor signals control FOXK1 nuclear localization and transcriptional activity.\",\n      \"evidence\": \"Phosphoproteomics, nuclear fractionation, DNA binding assays, genetic manipulation of mTORC1 and GSK3\",\n      \"pmids\": [\"29186685\", \"29861159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific GSK3 phosphorylation sites on FOXK1 not fully mapped\", \"Whether mTORC1 acts through additional intermediaries beyond PP2A\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The PP2A regulatory subunit B56 was identified as the specific mediator shuttling the mTORC1 signal to nuclear FOXK1, and insulin-stimulated reciprocal shuttling of FOXK1 (nuclear) versus FoxO1 (cytoplasmic) was demonstrated, establishing the Akt-mTOR-GSK3-PP2A(B56) axis as the complete signaling cascade.\",\n      \"evidence\": \"Nuclear-cytoplasmic transport inhibition, B56 genetic manipulation, live-cell imaging, RNA-seq in liver cells\",\n      \"pmids\": [\"29845697\", \"30952843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional phosphatases contribute in specific tissues\", \"Quantitative kinetics of FOXK1 shuttling not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A landmark metabolic study demonstrated that FOXK1 directly activates transcription of glycolytic enzymes (HK2, PFK, PKM2, LDHA) and pyruvate dehydrogenase kinases while repressing pyruvate dehydrogenase phosphatase, establishing FOXK1 as a master transcriptional driver of aerobic glycolysis (Warburg effect).\",\n      \"evidence\": \"Transcriptional assays, in vivo mouse models, primary human cell studies with comprehensive metabolic and gene expression analysis\",\n      \"pmids\": [\"30700909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FOXK1 and FOXK2 are fully redundant in glycolytic gene activation\", \"Direct versus indirect targets not genome-wide resolved at this stage\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"FOXK1 was established as a core chromatin-targeting subunit of the PR-DUB complex (BAP1/ASXL1/HCFC1/OGT) required for genome-wide BAP1 recruitment, H2AK119ub1 removal, and gene activation, while leukemia-associated ASXL1 truncation mutations were shown to disrupt the ASXL1–FOXK1 interaction and target gene expression.\",\n      \"evidence\": \"ChIP-seq, CRISPR knockout, mass spectrometry, allele-specific deletion, transcriptomic analysis\",\n      \"pmids\": [\"32747411\", \"32683582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FOXK1 and FOXK2 share all PR-DUB target sites\", \"How FOXK1 is itself recruited to specific genomic loci\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that FOXK1 interacts with 53BP1 in an ATM/CHK2-dependent manner during S phase and shifts DNA repair from NHEJ toward HR by displacing RIF1/PTIP extended FOXK1 function beyond transcription into DNA damage response regulation.\",\n      \"evidence\": \"Co-IP, live-cell imaging, siRNA, PARPi sensitivity and telomere fusion assays\",\n      \"pmids\": [\"32783940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FOXK1–53BP1 interaction unresolved\", \"Whether this function is FHA-domain dependent\", \"Relevance in non-cancer primary cells not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"HDAC3 was shown to protect FOXK1 from lysosomal degradation and co-occupy STAT1/STAT2 promoters with FOXK1, establishing a FOXK1-dependent transcriptional mechanism for innate antiviral immunity in macrophages.\",\n      \"evidence\": \"Co-IP, ChIP, CRISPR KO macrophages, viral challenge assays\",\n      \"pmids\": [\"35081346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of HDAC3-mediated protection from lysosomal degradation unknown\", \"Whether FOXK1 acts as activator or derepressor at STAT1/2 loci\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"FOXK1 was shown to repress Wnt/β-catenin signaling during cardiogenesis and to directly activate cardiac cell cycle genes CCNB1/CDK1, establishing its role as a key regulator of cardiac progenitor differentiation and cardiomyocyte proliferation.\",\n      \"evidence\": \"CRISPR KO embryoid bodies, ATAC-seq, RNA-seq, cardiomyocyte-specific KO, AAV9 rescue, in vivo MI model\",\n      \"pmids\": [\"37036809\", \"40128196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FOXK1 directly binds Wnt pathway gene promoters\", \"Redundancy with FOXK2 in cardiomyocytes not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CUT&Tag and conditional KO in osteoblasts confirmed that FOXK1 directly occupies glycolytic gene promoters in bone, and that its metabolic function is required for bone formation, generalizing the FOXK1–glycolysis axis to mesenchymal lineages.\",\n      \"evidence\": \"CUT&Tag, conditional Foxk1 KO in preosteoblasts, glycolysis assays, bone microstructure analysis, AAV rescue with glycolysis inhibitor\",\n      \"pmids\": [\"39232134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HIF1α mediates FOXK1's glycolytic effects in bone as in heart\", \"Contribution of FOXK2 in osteoblasts untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"KSHV ORF45 was found to bind the FOXK1 FHA domain through a phosphothreonine-containing linear motif, augmenting FOXK1 promoter binding and late viral gene transcription — revealing that viruses exploit FOXK1's FHA domain to hijack host transcriptional machinery.\",\n      \"evidence\": \"Co-IP, point mutagenesis of ORF45 threonine, ChIP, lytic reactivation assays\",\n      \"pmids\": [\"39494902\", \"39287387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cellular FHA-binding partners use the same motif\", \"Crystal structure of FOXK1 FHA–ligand complex not available\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"O-GlcNAcylation of FOXK1 was shown to be required for BAP1 recruitment to E2F target gene regulatory regions and for maintaining active chromatin; this modification is cell-cycle regulated, peaking at G1/S, and is essential for FOXK1-driven cellular transformation.\",\n      \"evidence\": \"O-GlcNAc site mutagenesis, ChIP-seq, chromatin modification analysis, proliferation/transformation assays, tumor growth assays\",\n      \"pmids\": [\"40593803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity and number of specific O-GlcNAcylated residues governing BAP1 interaction not fully mapped\", \"Whether O-GlcNAcylation affects FOXK1 interactions beyond BAP1\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"USP28-mediated deubiquitination was identified as a mechanism stabilizing FOXK1 protein levels, adding another layer of post-translational regulation distinct from HDAC3-mediated lysosomal protection.\",\n      \"evidence\": \"In vitro ubiquitination assay, co-IP, RNA-seq, xenograft model\",\n      \"pmids\": [\"39983825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase responsible for FOXK1 ubiquitination not identified\", \"Relationship between USP28 and HDAC3 protective mechanisms unclear\", \"Single-lab finding awaits independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the structural basis for FOXK1's context-dependent switching between transcriptional activation and repression; (2) the full catalog of O-GlcNAcylation sites and how each modifies specific protein interactions; (3) whether FOXK1 and FOXK2 are truly redundant at most genomic loci; and (4) how FOXK1's transcriptional, chromatin-remodeling, and DNA repair functions are coordinated in a cell-cycle-dependent manner.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structural model of FOXK1 in complex with chromatin or cofactors\", \"Genome-wide functional separation of FOXK1 vs FOXK2 not systematically performed\", \"Integration of metabolic, cell cycle, and DNA repair functions into a unified regulatory model lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 11, 22, 27, 28, 30, 35, 37, 38]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 6, 11, 22, 26, 27, 30, 33, 34, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 11, 24, 31, 35]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 6, 11, 22, 26, 27, 30, 33, 34, 38]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 5, 22, 27, 30, 31]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 23, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3, 25, 26]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [11, 31, 32]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5, 26, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\n      \"PR-DUB (BAP1/ASXL1/HCFC1/OGT)\",\n      \"NCoR/SMRT corepressor complex\",\n      \"SIN3 corepressor complex\",\n      \"REST/CoREST corepressor complex\"\n    ],\n    \"partners\": [\n      \"BAP1\",\n      \"ASXL1\",\n      \"SRF\",\n      \"FHL2\",\n      \"TP53BP1\",\n      \"SIN3A\",\n      \"HDAC3\",\n      \"OGT\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}