{"gene":"HOXB9","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2000,"finding":"BTG1 and BTG2 physically interact with HOXB9 (identified by yeast two-hybrid screening) and enhance HOXB9-mediated transcription in transfected cells. A HOXB9·BTG2 complex forms on a HOXB9-responsive target, and this interaction facilitates HOXB9 binding to DNA. The transcriptional activation is dependent on the N-terminal activation domain of HOXB9.","method":"Yeast two-hybrid screening, co-immunoprecipitation, transcription reporter assay, EMSA/DNA-binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid identification confirmed by reciprocal interaction assays, reporter assay, and DNA-binding assay in a single study with multiple orthogonal methods","pmids":["10617598"],"is_preprint":false},{"year":1997,"finding":"Targeted disruption of hoxb-9 in mice causes defects in first and second rib development and sternum morphogenesis; double mutants with hoxa-9 show synergistic (more severe) rib and sternal phenotypes, establishing that HOXB9 and HOXA9 function together in specification of thoracic skeletal elements.","method":"Targeted gene disruption in mice, genetic epistasis/double-mutant analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function mouse model with defined skeletal phenotype, synergistic double-mutant confirms paralog interaction","pmids":["9013929"],"is_preprint":false},{"year":1999,"finding":"Paralogous Hox genes Hoxa9, Hoxb9, and Hoxd9 are required for expansion and/or differentiation of mammary epithelial ductal system in response to pregnancy, demonstrated by triple mutant mice that cannot raise pups due to impaired mammary gland development.","method":"Targeted gene disruption in mice (triple mutant), histological analysis of mammary gland","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo loss-of-function with specific mammary gland phenotype, replicated across three paralogs","pmids":["9892669"],"is_preprint":false},{"year":1993,"finding":"Mouse HoxB9 expressed from a heat-shock promoter in Drosophila induces anterior-to-posterior homeotic transformations in larvae and adults, demonstrating functional similarity to Drosophila Abdominal-B and intermediate positional identity specification between Antennapedia and Abdominal-B.","method":"Transgenic Drosophila heat-shock expression, phenotypic analysis of homeotic transformations","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo functional assay in heterologous system, single study","pmids":["8105876"],"is_preprint":false},{"year":2009,"finding":"HOXB9 is a WNT/TCF target gene that mediates chemotactic invasion and colony outgrowth in lung adenocarcinoma cells; reduction of TCF activity attenuates brain and bone metastasis independently of effects on primary lung tumor growth, placing HOXB9 downstream of hyperactive WNT/TCF signaling in the metastatic program.","method":"Gene expression profiling, shRNA knockdown, in vivo metastasis assays (brain/bone colonization in mice)","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo functional metastasis assays with shRNA knockdown, multiple cell lines, pathway epistasis established","pmids":["19576624"],"is_preprint":false},{"year":2009,"finding":"HOXB9 as a transcription factor induces expression of angiogenic factors (VEGF, bFGF, IL-8, ANGPTL-2), ErbB ligands (amphiregulin, epiregulin, neuregulins), and TGF-β, leading to increased cell motility, EMT acquisition, and in vivo tumor growth with lung metastasis in breast cancer.","method":"Overexpression in breast cancer cell lines, in vivo xenograft/metastasis assay, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo xenograft with lung metastasis, multiple downstream targets characterized, consistent with mechanistic follow-up papers","pmids":["20080567"],"is_preprint":false},{"year":2016,"finding":"PCAF acetyltransferase interacts with and acetylates HOXB9 at lysine 27 (K27) both in vivo and in vitro; this acetylation is reversed by SIRT1 deacetylase. AcK27-HOXB9 suppresses transcription of its target gene JMJD6 by occupying the JMJD6 promoter, decreasing lung cancer cell migration and tumor growth compared to non-acetylated HOXB9.","method":"Co-immunoprecipitation, in vitro acetylation assay, site-directed mutagenesis (K27), ChIP assay, luciferase reporter assay, xenograft mouse model","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro and in vivo acetylation with mutagenesis, writer (PCAF) and eraser (SIRT1) identified, ChIP and functional assays, multiple orthogonal methods","pmids":["27613418"],"is_preprint":false},{"year":2018,"finding":"Acetylation of HOXB9 at K27 causes its translocation from the nucleus to the cytoplasm, switching its function: non-acetylated HOXB9 promotes EZH2 expression and colon cancer progression, while AcK27-HOXB9 suppresses EZH2 transcription by relocating out of the nucleus.","method":"Subcellular fractionation, immunofluorescence, luciferase reporter assay, Western blot, immunohistochemistry","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular localization with functional consequence shown, luciferase assay for target gene, single lab","pmids":["29654889"],"is_preprint":false},{"year":2011,"finding":"HOXB9 gene transcription is activated by estrogen (E2) through estrogen receptors ERα and ERβ binding to estrogen-response elements (EREs) in the HOXB9 promoter; histone methylases MLL1 and MLL3 also bind to HOXB9 EREs and are required for E2-mediated transcriptional activation.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays identifying EREs, ERs, MLL1/3 as regulators; single lab, two orthogonal methods","pmids":["21428455"],"is_preprint":false},{"year":2016,"finding":"Bisphenol-A (BPA) induces HOXB9 expression via EREs in the HOXB9 promoter, requiring estrogen receptors and co-regulators MLL3 histone methylase, CBP/P300 histone acetylases; these factors are recruited to HOXB9 promoter EREs in the presence of BPA, leading to chromatin modification (histone methylation and acetylation) and gene activation.","method":"Luciferase reporter assay, ChIP assay, in vivo animal experiment (ovariectomized rats), cell-based expression assays","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms factor recruitment, in vivo validation included, single lab","pmids":["27182052"],"is_preprint":false},{"year":2007,"finding":"In Hodgkin lymphoma cells, HOXB9 expression is regulated by E2F3A (activator) and BMI1 (repressor); a constitutively active ERK5 pathway represses BMI1, thereby increasing HOXB9 expression. HOXB9 knockdown and overexpression influence both proliferation and apoptosis in HL cells.","method":"RT-PCR, microarray profiling, knockdown/overexpression functional assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pathway placement via expression manipulation with functional readouts, ERK5-BMI1-HOXB9 axis identified, single lab","pmids":["17148583"],"is_preprint":false},{"year":2008,"finding":"The Hoxb9 promoter forms secondary DNA structures that regulate promoter activity; FBXL10 was identified as a protein that specifically binds the secondary-structured promoter DNA and affects Hoxb9 promoter activity.","method":"Promoter activity assays in cultured cells, nuclear extract binding assays, candidate gene isolation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional promoter assay with identified binding protein FBXL10, secondary structure formation linked to expression, single lab","pmids":["18276649"],"is_preprint":false},{"year":2012,"finding":"HOXB9 binds to the promoters of tumor growth and angiogenic factors and regulates their expression; the HOXB9 homeodomain is required for this transcriptional regulatory activity and for 3D colony formation in soft agar.","method":"ChIP assay (promoter binding), reporter assays, homeodomain deletion/mutation analysis, soft agar colony formation assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence for promoter occupancy, homeodomain mutagenesis with functional readout, single lab","pmids":["22863320"],"is_preprint":false},{"year":2014,"finding":"E2F1 directly binds the HOXB9 promoter region (–404 to –392) and transcriptionally activates HOXB9 in breast cancer cells; CDK4/6 inhibition reduces E2F1 and consequently reduces HOXB9 and its downstream target genes.","method":"Dual luciferase reporter assay, EMSA, ChIP, mutation analysis of the TFBS, Q-PCR","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and ChIP confirm E2F1 binding to HOXB9 promoter, multiple orthogonal methods, single lab","pmids":["25136922"],"is_preprint":false},{"year":2015,"finding":"HOXB9 promotes invasion and metastasis in pancreatic ductal adenocarcinoma through downregulation of E-cadherin; Kindlin-2, itself upregulated by TGF-β1, promotes PDAC progression by downregulating HOXB9 and E-cadherin, placing HOXB9 downstream of a TGF-β1/Kindlin-2 axis.","method":"Knockdown/overexpression in PDAC cells, Western blot, migration/invasion assays, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pathway epistasis established in cell lines and in vivo, single lab","pmids":["25724625"],"is_preprint":false},{"year":2014,"finding":"HOXB9 promotes EMT in hepatocellular carcinoma cells; knockdown of HOXB9 decreased migration and invasion, while overexpression increased them. TGF-β1 pathway activation is required for HOXB9-induced EMT in HCC cells.","method":"shRNA knockdown, overexpression, migration/invasion assays, Western blot for EMT markers","journal":"Clinical and experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single-method functional characterization without direct mechanistic binding or pathway reconstitution","pmids":["25081022"],"is_preprint":false},{"year":2018,"finding":"HOXB9 directly binds the promoter of microRNA-765 and facilitates its transcription; miR-765 in turn targets FOXA2, reducing FOXA2 levels and promoting cancer stem cell self-renewal and ER stress resistance in melanoma.","method":"ChIP assay, luciferase reporter assay, overexpression/knockdown, xenograft mouse model","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms HOXB9 promoter occupancy on miR-765, luciferase validates, downstream target FOXA2 identified; single lab","pmids":["29408459"],"is_preprint":false},{"year":2018,"finding":"HOXB9 promotes E2F3 expression by directly targeting its promoter in endometrial cancer cells; knockdown of E2F3 abolishes HOXB9-enhanced cell migration, placing E2F3 downstream of HOXB9 in this cancer context.","method":"ChIP assay, luciferase reporter assay, siRNA knockdown, migration assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct promoter targeting, epistasis shown by E2F3 rescue experiment; single lab","pmids":["29724991"],"is_preprint":false},{"year":2022,"finding":"AMPKα phosphorylates HOXB9 at threonine 133 (T133), promoting E3 ligase Praja2-mediated ubiquitination and proteasomal degradation of HOXB9 in lung adenocarcinoma cells. Blocking T133 phosphorylation (HOXB9 T133A mutant or AMPKα1/2 depletion) stabilizes HOXB9 and upregulates its target gene KRAS, promoting tumor growth.","method":"In vitro kinase assay, site-directed mutagenesis (T133A), co-immunoprecipitation, xenograft mouse model, LUAD patient sample analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — kinase substrate identification with mutagenesis, E3 ligase (Praja2) identified, in vivo validation, KRAS identified as downstream target; multiple orthogonal methods","pmids":["36001969"],"is_preprint":false},{"year":2022,"finding":"HOXB9 directly regulates cell cycle progression in pancreatic cancer by binding the RBL2 promoter to upregulate RBL2 and inhibiting c-Myc, causing G0/G1 arrest; DNMT1 suppresses HOXB9 expression by promoting methylation of its promoter.","method":"ChIP-qPCR, luciferase reporter assay, flow cytometry (cell cycle), cell cycle PCR array, xenograft and PDX mouse models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct HOXB9-RBL2 promoter binding; DNMT1 epigenetic regulation supported; in vivo validation included; single lab","pmids":["35182659"],"is_preprint":false},{"year":2015,"finding":"GalNAc-T14 increases β-catenin protein stability, leading to activated WNT signaling that induces HOXB9 expression; pharmacological inhibition of β-catenin suppresses HOXB9 expression and invasion, placing HOXB9 downstream of GalNAc-T14/WNT/β-catenin in lung cancer metastasis.","method":"Microarray, Western blot, pharmacological inhibition of β-catenin, invasion assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pathway epistasis via pharmacological inhibition, microarray and biochemical confirmation; single lab","pmids":["26544896"],"is_preprint":false},{"year":2019,"finding":"GRP78 chaperones LRP6, promoting its maturation; knockdown of GRP78 leads to LRP6 misfolding and ERAD-dependent degradation, reducing mature LRP6 levels and thereby suppressing Wnt/HOXB9 signaling and HCC invasion/metastasis. HOXB9 overexpression rescues invasion/metastasis upon GRP78 knockdown.","method":"Knockdown (GRP78), overexpression (HOXB9), Western blot, co-immunoprecipitation, invasion/metastasis assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — epistasis rescue experiment with knockdown/overexpression, molecular mechanism via LRP6 maturation proposed and supported; single lab","pmids":["31310747"],"is_preprint":false},{"year":2015,"finding":"The hexapeptide motif of HOXB9 acts as a negative regulatory element ('brake') on its MET-inducing and tumor-suppressive activity in gastric carcinoma; a HOXB9 mutant lacking the hexapeptide motif shows more potent MET induction and tumor suppression than wild-type HOXB9.","method":"Site-directed mutagenesis (hexapeptide motif deletion), overexpression in gastric cancer cell lines, migration/invasion assays, in vivo xenograft","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with functional readout in vitro and in vivo; single lab","pmids":["26536658"],"is_preprint":false},{"year":2020,"finding":"HOXB9-dependent expression of MMP9 in NSCLC cells leads to reduced expression of junctional proteins in vascular endothelial cells and enhanced transmigration of tumor cells through an in vitro blood-brain barrier model, establishing a mechanism for HOXB9-driven brain metastasis.","method":"In vitro BBB model (endothelial monolayer), shRNA knockdown and overexpression of HOXB9, measurement of junctional proteins, transmigration assay, in vivo brain metastasis in mice","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro BBB functional model with knockdown/overexpression, MMP9 identified as mechanistic intermediate; single lab","pmids":["33411683"],"is_preprint":false},{"year":2023,"finding":"HOXB9 interacts with PBX2 to form a heterodimer that transcriptionally upregulates CDK6, promoting G1-to-S phase cell cycle progression and gastric cancer cell division; HOXB9 depletion causes G1 arrest that is phenocopied by CDK6 knockdown, and CDK6 knockdown reverses HOXB9-driven tumor growth.","method":"Co-immunoprecipitation (HOXB9-PBX2), ChIP, luciferase reporter assay, shRNA knockdown, cell cycle analysis, xenograft mouse model","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifies HOXB9-PBX2 complex, ChIP and luciferase confirm CDK6 as direct target, epistasis rescue with CDK6 KD, in vivo validation; multiple orthogonal methods","pmids":["37272544"],"is_preprint":false},{"year":2016,"finding":"HOXB9 expression is triggered by amino acid deprivation via activating transcription factor 4 (ATF4) in activated T cells; HOXB9 in turn suppresses NF-κB, NFAT, and AP-1 activities, attenuating selective cytokine production in response to amino acid starvation.","method":"siRNA knockdown, overexpression, reporter assays for NF-κB/NFAT/AP-1, amino acid deprivation experiments","journal":"Immunology and cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional assays without direct binding evidence for HOXB9 on NF-κB/NFAT targets; ATF4 regulation inferred","pmids":["26926958"],"is_preprint":false},{"year":2024,"finding":"HOXB9 directly binds to the promoter of SLC7A11 and transcriptionally upregulates its expression; cold atmospheric plasma (CAP) promotes HOXB9 interaction with PCAF, enhancing HOXB9 acetylation, which affects its ubiquitination and protein stability, ultimately downregulating HOXB9/SLC7A11 and promoting ferroptosis in lung cancer cells.","method":"Luciferase assay, ChIP, co-immunoprecipitation (HOXB9-PCAF), ubiquitination assay, overexpression/knockdown, in vivo xenograft","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct HOXB9-SLC7A11 promoter binding, PCAF interaction confirmed by Co-IP, in vivo validation; single lab","pmids":["39127016"],"is_preprint":false},{"year":2025,"finding":"TRIM11 acts as an E3 ubiquitin ligase that ubiquitinates HOXB9, promoting its degradation and reversing HOXB9-induced NF-κB pathway activation; simultaneous downregulation of TRIM11 and HOXB9 balances inflammation and apoptosis responses in LPS-stimulated THP-1 cells.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, Western blot, flow cytometry, ELISA","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ubiquitination interaction supported by Co-IP and functional assays, TRIM11 identified as E3 ligase for HOXB9; single lab","pmids":["39903348"],"is_preprint":false},{"year":2016,"finding":"Dynamic subcellular localization of HOXB9 protein was characterized during mammalian early embryonic development by immunofluorescence: HOXB9 is mainly nuclear from immature oocyte to blastocyst stage in both mouse and bovine, with trophoblastic cells showing strong nuclear staining while inner cell mass/epiblast cells show dynamic variation in localization including cytoplasmic pools, and HOXB9 is detected in apical vacuoles of mouse visceral endoderm cells.","method":"Immunofluorescence microscopy across developmental stages (mouse and bovine), subcellular localization analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — systematic immunofluorescence across developmental stages in two species, conserved pattern; no functional consequence directly established","pmids":["27798681"],"is_preprint":false},{"year":2025,"finding":"HOXB9 directly binds the SDC4 promoter (site 2) and activates SDC4 transcription, as confirmed by ChIP and dual-luciferase reporter assay. HOXB9 overexpression promotes SDC4 expression and PKCα activation, leading to reduced tight junction proteins and BBB disruption under ischemic conditions.","method":"ChIP assay, dual-luciferase reporter assay, overexpression, TEER assay, immunofluorescence, in vivo MCAO rat model","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP and luciferase confirm HOXB9-SDC4 promoter binding, in vivo validation included; single lab","pmids":["40571266"],"is_preprint":false},{"year":2024,"finding":"HOXB9 directly binds the promoter of MMP12 and transcriptionally activates it in laryngeal squamous cell carcinoma; CRISPR/Cas9 knockout of HOXB9 suppresses cell proliferation, migration, invasion and reduces MMP12 expression.","method":"CRISPR/Cas9 knockout, ChIP, dual-luciferase reporter assay, microarray, Western blot, immunohistochemistry, in vivo xenograft","journal":"Functional & integrative genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct HOXB9-MMP12 promoter binding, CRISPR knockout with functional readout; single lab","pmids":["38632141"],"is_preprint":false},{"year":2024,"finding":"HOXB9 directly binds the SPP1 promoter and transcriptionally upregulates SPP1 expression, protecting osteosarcoma cells from death under glucose starvation conditions.","method":"ChIP assay, luciferase reporter assay, overexpression/knockdown, cell viability assay under glucose deprivation","journal":"Biochemical pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and luciferase confirm promoter binding, but study is single lab with limited mechanistic depth","pmids":["38621423"],"is_preprint":false},{"year":2026,"finding":"IGF2BP3 binds and stabilizes HOXB9 mRNA in an m6A-dependent manner, increasing HOXB9 protein levels; HOXB9 then transcriptionally activates IL15RA expression, and IL-15/IL15RA signaling promotes migration, invasion, and in vivo metastasis of TNBC cells.","method":"RNA immunoprecipitation (RIP), Western blot, m6A assay, overexpression/knockdown, in vivo metastasis model","journal":"Functional & integrative genomics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP confirms IGF2BP3-HOXB9 mRNA binding, m6A dependence shown, downstream IL15RA pathway functionally validated; single lab","pmids":["42168464"],"is_preprint":false}],"current_model":"HOXB9 is a homeodomain transcription factor that directly binds target gene promoters (including JMJD6, RBL2, E2F3, CDK6 via PBX2 heterodimer, miR-765, MMP12, SLC7A11, SPP1, IL15RA, SDC4) to regulate embryonic patterning, mammary gland development, and cancer progression; its activity is modulated by post-translational modifications—acetylation at K27 by PCAF (reversed by SIRT1) shifts HOXB9 from nucleus to cytoplasm and suppresses oncogenic targets, while AMPKα-mediated phosphorylation at T133 triggers Praja2 E3 ligase-dependent proteasomal degradation and TRIM11 promotes its ubiquitination—and its transcription is activated by WNT/TCF, E2F1, estrogen receptors with MLL1/MLL3, and ERK5 (via BMI1 repression), and enhanced by BTG1/BTG2 co-factors that stabilize its DNA binding."},"narrative":{"mechanistic_narrative":"HOXB9 is a homeodomain transcription factor that specifies positional and skeletal identity during development and is repeatedly co-opted as a driver of cancer invasion and metastasis [PMID:9013929, PMID:19576624, PMID:20080567]. In the embryo it acts together with paralogous Hox9 genes: loss of Hoxb9 disrupts rib and sternum morphogenesis with synergistic defects in Hoxa9 double mutants [PMID:9013929], and Hoxa9/Hoxb9/Hoxd9 triple mutants fail in pregnancy-induced mammary ductal expansion [PMID:9892669], consistent with HOXB9's intrinsic capacity to specify intermediate antero-posterior identity when expressed heterologously [PMID:8105876]. Its transcriptional output depends on the homeodomain for promoter occupancy [PMID:22863320] and is enhanced by the BTG1/BTG2 co-factors, which bind HOXB9 and stabilize its DNA binding through its N-terminal activation domain [PMID:10617598]; in gastric cancer HOXB9 partners with PBX2 to form a heterodimer that activates CDK6 and drives G1-to-S progression [PMID:37272544]. Across multiple tumor types HOXB9 directly binds and activates target promoters to promote proliferation, EMT, angiogenesis, and metastasis, including JMJD6 [PMID:27613418], E2F3 [PMID:29724991], miR-765 [PMID:29408459], MMP12 [PMID:38632141], SLC7A11 [PMID:39127016], SDC4 [PMID:40571266], and IL15RA [PMID:42168464], and induces angiogenic and ErbB-ligand programs [PMID:20080567]; conversely it can act as a tumor suppressor by binding the RBL2 promoter to enforce G0/G1 arrest [PMID:35182659]. HOXB9 abundance, localization, and activity are tightly controlled by post-translational modification: PCAF acetylates HOXB9 at K27 (reversed by SIRT1), driving nuclear-to-cytoplasmic relocation that suppresses oncogenic targets such as JMJD6 and EZH2 [PMID:27613418, PMID:29654889], while AMPKα phosphorylation at T133 licenses Praja2-mediated ubiquitination and proteasomal degradation that limits KRAS induction [PMID:36001969], and TRIM11 ubiquitinates HOXB9 to reverse its NF-κB-activating activity [PMID:39903348]. HOXB9 transcription is itself a convergence point for WNT/β-catenin/TCF [PMID:19576624, PMID:26544896], E2F1 [PMID:25136922], estrogen-receptor/MLL signaling [PMID:21428455], and an ERK5–BMI1 axis [PMID:17148583], and its mRNA is stabilized by IGF2BP3 in an m6A-dependent manner [PMID:42168464].","teleology":[{"year":1993,"claim":"Established that mammalian HOXB9 is a bona fide positional-identity selector by showing it can impose homeotic transformations in a heterologous organism.","evidence":"Heat-shock-driven mouse HoxB9 expression in transgenic Drosophila scoring homeotic transformations","pmids":["8105876"],"confidence":"Medium","gaps":["Heterologous system does not define endogenous mammalian targets","No molecular partners or DNA targets identified"]},{"year":1997,"claim":"Defined HOXB9's endogenous developmental role and its functional cooperativity with a paralog by genetic loss-of-function.","evidence":"Targeted disruption of hoxb-9 in mice with hoxa-9 double-mutant epistasis analysis of rib/sternum phenotypes","pmids":["9013929"],"confidence":"High","gaps":["Molecular basis of paralog synergy not resolved","Direct target genes in skeletal patterning unknown"]},{"year":1999,"claim":"Extended HOXB9 function beyond skeletal patterning to organ morphogenesis, showing redundancy across Hox9 paralogs in mammary development.","evidence":"Hoxa9/Hoxb9/Hoxd9 triple-mutant mice with histological mammary gland analysis","pmids":["9892669"],"confidence":"High","gaps":["Does not separate HOXB9-specific from shared paralog contributions","Downstream effectors in ductal expansion not identified"]},{"year":2000,"claim":"Provided the first direct biochemical mechanism for HOXB9 transactivation by identifying co-factors that enhance its DNA binding.","evidence":"Yeast two-hybrid, co-IP, EMSA, and reporter assays defining BTG1/BTG2 interaction and N-terminal activation domain dependence","pmids":["10617598"],"confidence":"High","gaps":["Physiological target genes co-regulated by BTG proteins not defined","Structural basis of binding enhancement unknown"]},{"year":2007,"claim":"Placed HOXB9 transcription within an upstream signaling hierarchy in lymphoma and linked it to proliferation/apoptosis.","evidence":"Expression profiling and knockdown/overexpression mapping an ERK5–BMI1–E2F3A axis controlling HOXB9 in Hodgkin lymphoma cells","pmids":["17148583"],"confidence":"Medium","gaps":["No direct binding of E2F3A/BMI1 to HOXB9 promoter shown","HOXB9 effector targets in this context not identified"]},{"year":2009,"claim":"Identified HOXB9 as a metastasis-driving WNT/TCF effector and characterized its angiogenic/EMT transcriptional program.","evidence":"WNT/TCF target identification with shRNA knockdown and in vivo brain/bone metastasis assays; overexpression with xenograft metastasis and target-gene profiling","pmids":["19576624","20080567"],"confidence":"High","gaps":["Direct promoter occupancy on individual angiogenic targets not established here","Mechanism distinguishing primary growth from metastasis incomplete"]},{"year":2012,"claim":"Demonstrated the homeodomain is required for HOXB9 promoter occupancy and oncogenic transformation activity.","evidence":"ChIP, reporter assays, homeodomain mutagenesis, and soft-agar colony formation","pmids":["22863320"],"confidence":"Medium","gaps":["Single lab","Co-factor requirements for site selection not defined"]},{"year":2011,"claim":"Defined hormone-responsive transcriptional control of HOXB9 by estrogen receptors and chromatin-modifying co-regulators.","evidence":"Reporter assays, ChIP, and siRNA showing ERα/ERβ and MLL1/MLL3 binding to HOXB9 promoter EREs (extended to BPA/CBP-P300 in 2016)","pmids":["21428455","27182052"],"confidence":"Medium","gaps":["Single lab","In vivo physiological relevance of ER-driven HOXB9 in normal tissue limited"]},{"year":2014,"claim":"Identified E2F1 and CDK4/6 signaling as direct upstream activators of HOXB9 transcription in breast cancer.","evidence":"EMSA, ChIP, promoter mutation, and dual-luciferase mapping E2F1 binding at –404/–392","pmids":["25136922"],"confidence":"Medium","gaps":["Single lab","Generalizability beyond breast cancer untested"]},{"year":2016,"claim":"Established acetylation as a master switch governing HOXB9 oncogenic versus suppressive output by defining its writer, eraser, and site.","evidence":"In vitro/in vivo acetylation assays, K27 mutagenesis, PCAF/SIRT1 identification, ChIP on JMJD6, and xenograft (extended in 2018 to nuclear-cytoplasmic relocation and EZH2)","pmids":["27613418","29654889"],"confidence":"High","gaps":["Nuclear export machinery responding to AcK27 not identified","Determinants selecting which targets are switched off unclear"]},{"year":2015,"claim":"Mapped multiple upstream pathways and an intramolecular brake controlling HOXB9 activity across cancer types.","evidence":"Pathway epistasis for GalNAc-T14/WNT/β-catenin and TGFβ1/Kindlin-2 axes; hexapeptide-deletion mutagenesis defining a negative regulatory motif in gastric cancer","pmids":["26544896","25724625","26536658","25081022"],"confidence":"Medium","gaps":["Context-dependence of oncogenic vs suppressive HOXB9 not mechanistically unified","Some links rely on single-method functional assays"]},{"year":2018,"claim":"Expanded the direct HOXB9 target repertoire to non-coding and proliferative effectors driving stemness and migration.","evidence":"ChIP and luciferase validating direct binding to miR-765 and E2F3 promoters with knockdown/rescue and xenografts","pmids":["29408459","29724991"],"confidence":"Medium","gaps":["Single lab per target","Cross-tumor conservation of these targets untested"]},{"year":2022,"claim":"Revealed a phosphodegron controlling HOXB9 stability and identified its kinase and E3 ligase, linking metabolic signaling to HOXB9-driven KRAS expression.","evidence":"In vitro kinase assay, T133A mutagenesis, co-IP, AMPKα/Praja2 identification, KRAS target validation, and xenograft (RBL2 cell-cycle target defined same year)","pmids":["36001969","35182659"],"confidence":"High","gaps":["Stoichiometry of AMPK–Praja2 coupling unresolved","How phosphorylation/acetylation switches are integrated unknown"]},{"year":2023,"claim":"Identified PBX2 as a direct heterodimerization partner that channels HOXB9 to a CDK6-driven proliferation program.","evidence":"Reciprocal co-IP, ChIP, luciferase on CDK6, knockdown with CDK6 epistasis rescue, and xenograft in gastric cancer","pmids":["37272544"],"confidence":"High","gaps":["Whether PBX2 partnership generalizes to other HOXB9 targets unknown","Structural basis of the heterodimer not resolved"]},{"year":2024,"claim":"Connected HOXB9 to redox/ferroptosis and barrier-disruption programs and refined PTM control of its stability.","evidence":"ChIP/luciferase on SLC7A11, MMP12, SPP1, and SDC4 promoters; CAP-induced PCAF-HOXB9 acetylation and ubiquitination assays; in vivo barrier and xenograft models","pmids":["39127016","38632141","38621423","40571266"],"confidence":"Medium","gaps":["Single lab per target","Interplay between acetylation and ubiquitination on stability not fully resolved"]},{"year":2026,"claim":"Added post-transcriptional m6A control of HOXB9 abundance feeding an IL-15 signaling axis in metastasis.","evidence":"RIP, m6A assays, and metastasis models showing IGF2BP3 stabilizes HOXB9 mRNA driving IL15RA transcription","pmids":["42168464"],"confidence":"Medium","gaps":["Single lab","Relative contribution of mRNA vs protein-level control to HOXB9 levels unknown"]},{"year":null,"claim":"How HOXB9 selects between oncogenic and tumor-suppressive transcriptional programs across tissues, and how its competing acetylation, phosphorylation, ubiquitination, and m6A controls are integrated in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking PTM state to target-gene selection","Structural basis of HOXB9 cofactor 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(identified by yeast two-hybrid screening) and enhance HOXB9-mediated transcription in transfected cells. A HOXB9·BTG2 complex forms on a HOXB9-responsive target, and this interaction facilitates HOXB9 binding to DNA. The transcriptional activation is dependent on the N-terminal activation domain of HOXB9.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, transcription reporter assay, EMSA/DNA-binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid identification confirmed by reciprocal interaction assays, reporter assay, and DNA-binding assay in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"10617598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Targeted disruption of hoxb-9 in mice causes defects in first and second rib development and sternum morphogenesis; double mutants with hoxa-9 show synergistic (more severe) rib and sternal phenotypes, establishing that HOXB9 and HOXA9 function together in specification of thoracic skeletal elements.\",\n      \"method\": \"Targeted gene disruption in mice, genetic epistasis/double-mutant analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function mouse model with defined skeletal phenotype, synergistic double-mutant confirms paralog interaction\",\n      \"pmids\": [\"9013929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Paralogous Hox genes Hoxa9, Hoxb9, and Hoxd9 are required for expansion and/or differentiation of mammary epithelial ductal system in response to pregnancy, demonstrated by triple mutant mice that cannot raise pups due to impaired mammary gland development.\",\n      \"method\": \"Targeted gene disruption in mice (triple mutant), histological analysis of mammary gland\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo loss-of-function with specific mammary gland phenotype, replicated across three paralogs\",\n      \"pmids\": [\"9892669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Mouse HoxB9 expressed from a heat-shock promoter in Drosophila induces anterior-to-posterior homeotic transformations in larvae and adults, demonstrating functional similarity to Drosophila Abdominal-B and intermediate positional identity specification between Antennapedia and Abdominal-B.\",\n      \"method\": \"Transgenic Drosophila heat-shock expression, phenotypic analysis of homeotic transformations\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo functional assay in heterologous system, single study\",\n      \"pmids\": [\"8105876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HOXB9 is a WNT/TCF target gene that mediates chemotactic invasion and colony outgrowth in lung adenocarcinoma cells; reduction of TCF activity attenuates brain and bone metastasis independently of effects on primary lung tumor growth, placing HOXB9 downstream of hyperactive WNT/TCF signaling in the metastatic program.\",\n      \"method\": \"Gene expression profiling, shRNA knockdown, in vivo metastasis assays (brain/bone colonization in mice)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo functional metastasis assays with shRNA knockdown, multiple cell lines, pathway epistasis established\",\n      \"pmids\": [\"19576624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HOXB9 as a transcription factor induces expression of angiogenic factors (VEGF, bFGF, IL-8, ANGPTL-2), ErbB ligands (amphiregulin, epiregulin, neuregulins), and TGF-β, leading to increased cell motility, EMT acquisition, and in vivo tumor growth with lung metastasis in breast cancer.\",\n      \"method\": \"Overexpression in breast cancer cell lines, in vivo xenograft/metastasis assay, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo xenograft with lung metastasis, multiple downstream targets characterized, consistent with mechanistic follow-up papers\",\n      \"pmids\": [\"20080567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PCAF acetyltransferase interacts with and acetylates HOXB9 at lysine 27 (K27) both in vivo and in vitro; this acetylation is reversed by SIRT1 deacetylase. AcK27-HOXB9 suppresses transcription of its target gene JMJD6 by occupying the JMJD6 promoter, decreasing lung cancer cell migration and tumor growth compared to non-acetylated HOXB9.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, site-directed mutagenesis (K27), ChIP assay, luciferase reporter assay, xenograft mouse model\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro and in vivo acetylation with mutagenesis, writer (PCAF) and eraser (SIRT1) identified, ChIP and functional assays, multiple orthogonal methods\",\n      \"pmids\": [\"27613418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Acetylation of HOXB9 at K27 causes its translocation from the nucleus to the cytoplasm, switching its function: non-acetylated HOXB9 promotes EZH2 expression and colon cancer progression, while AcK27-HOXB9 suppresses EZH2 transcription by relocating out of the nucleus.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, luciferase reporter assay, Western blot, immunohistochemistry\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular localization with functional consequence shown, luciferase assay for target gene, single lab\",\n      \"pmids\": [\"29654889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HOXB9 gene transcription is activated by estrogen (E2) through estrogen receptors ERα and ERβ binding to estrogen-response elements (EREs) in the HOXB9 promoter; histone methylases MLL1 and MLL3 also bind to HOXB9 EREs and are required for E2-mediated transcriptional activation.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays identifying EREs, ERs, MLL1/3 as regulators; single lab, two orthogonal methods\",\n      \"pmids\": [\"21428455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Bisphenol-A (BPA) induces HOXB9 expression via EREs in the HOXB9 promoter, requiring estrogen receptors and co-regulators MLL3 histone methylase, CBP/P300 histone acetylases; these factors are recruited to HOXB9 promoter EREs in the presence of BPA, leading to chromatin modification (histone methylation and acetylation) and gene activation.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, in vivo animal experiment (ovariectomized rats), cell-based expression assays\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms factor recruitment, in vivo validation included, single lab\",\n      \"pmids\": [\"27182052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Hodgkin lymphoma cells, HOXB9 expression is regulated by E2F3A (activator) and BMI1 (repressor); a constitutively active ERK5 pathway represses BMI1, thereby increasing HOXB9 expression. HOXB9 knockdown and overexpression influence both proliferation and apoptosis in HL cells.\",\n      \"method\": \"RT-PCR, microarray profiling, knockdown/overexpression functional assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pathway placement via expression manipulation with functional readouts, ERK5-BMI1-HOXB9 axis identified, single lab\",\n      \"pmids\": [\"17148583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The Hoxb9 promoter forms secondary DNA structures that regulate promoter activity; FBXL10 was identified as a protein that specifically binds the secondary-structured promoter DNA and affects Hoxb9 promoter activity.\",\n      \"method\": \"Promoter activity assays in cultured cells, nuclear extract binding assays, candidate gene isolation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional promoter assay with identified binding protein FBXL10, secondary structure formation linked to expression, single lab\",\n      \"pmids\": [\"18276649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HOXB9 binds to the promoters of tumor growth and angiogenic factors and regulates their expression; the HOXB9 homeodomain is required for this transcriptional regulatory activity and for 3D colony formation in soft agar.\",\n      \"method\": \"ChIP assay (promoter binding), reporter assays, homeodomain deletion/mutation analysis, soft agar colony formation assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence for promoter occupancy, homeodomain mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"22863320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"E2F1 directly binds the HOXB9 promoter region (–404 to –392) and transcriptionally activates HOXB9 in breast cancer cells; CDK4/6 inhibition reduces E2F1 and consequently reduces HOXB9 and its downstream target genes.\",\n      \"method\": \"Dual luciferase reporter assay, EMSA, ChIP, mutation analysis of the TFBS, Q-PCR\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and ChIP confirm E2F1 binding to HOXB9 promoter, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"25136922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HOXB9 promotes invasion and metastasis in pancreatic ductal adenocarcinoma through downregulation of E-cadherin; Kindlin-2, itself upregulated by TGF-β1, promotes PDAC progression by downregulating HOXB9 and E-cadherin, placing HOXB9 downstream of a TGF-β1/Kindlin-2 axis.\",\n      \"method\": \"Knockdown/overexpression in PDAC cells, Western blot, migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pathway epistasis established in cell lines and in vivo, single lab\",\n      \"pmids\": [\"25724625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HOXB9 promotes EMT in hepatocellular carcinoma cells; knockdown of HOXB9 decreased migration and invasion, while overexpression increased them. TGF-β1 pathway activation is required for HOXB9-induced EMT in HCC cells.\",\n      \"method\": \"shRNA knockdown, overexpression, migration/invasion assays, Western blot for EMT markers\",\n      \"journal\": \"Clinical and experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single-method functional characterization without direct mechanistic binding or pathway reconstitution\",\n      \"pmids\": [\"25081022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HOXB9 directly binds the promoter of microRNA-765 and facilitates its transcription; miR-765 in turn targets FOXA2, reducing FOXA2 levels and promoting cancer stem cell self-renewal and ER stress resistance in melanoma.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, overexpression/knockdown, xenograft mouse model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms HOXB9 promoter occupancy on miR-765, luciferase validates, downstream target FOXA2 identified; single lab\",\n      \"pmids\": [\"29408459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HOXB9 promotes E2F3 expression by directly targeting its promoter in endometrial cancer cells; knockdown of E2F3 abolishes HOXB9-enhanced cell migration, placing E2F3 downstream of HOXB9 in this cancer context.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, siRNA knockdown, migration assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct promoter targeting, epistasis shown by E2F3 rescue experiment; single lab\",\n      \"pmids\": [\"29724991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AMPKα phosphorylates HOXB9 at threonine 133 (T133), promoting E3 ligase Praja2-mediated ubiquitination and proteasomal degradation of HOXB9 in lung adenocarcinoma cells. Blocking T133 phosphorylation (HOXB9 T133A mutant or AMPKα1/2 depletion) stabilizes HOXB9 and upregulates its target gene KRAS, promoting tumor growth.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (T133A), co-immunoprecipitation, xenograft mouse model, LUAD patient sample analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — kinase substrate identification with mutagenesis, E3 ligase (Praja2) identified, in vivo validation, KRAS identified as downstream target; multiple orthogonal methods\",\n      \"pmids\": [\"36001969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HOXB9 directly regulates cell cycle progression in pancreatic cancer by binding the RBL2 promoter to upregulate RBL2 and inhibiting c-Myc, causing G0/G1 arrest; DNMT1 suppresses HOXB9 expression by promoting methylation of its promoter.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assay, flow cytometry (cell cycle), cell cycle PCR array, xenograft and PDX mouse models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct HOXB9-RBL2 promoter binding; DNMT1 epigenetic regulation supported; in vivo validation included; single lab\",\n      \"pmids\": [\"35182659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GalNAc-T14 increases β-catenin protein stability, leading to activated WNT signaling that induces HOXB9 expression; pharmacological inhibition of β-catenin suppresses HOXB9 expression and invasion, placing HOXB9 downstream of GalNAc-T14/WNT/β-catenin in lung cancer metastasis.\",\n      \"method\": \"Microarray, Western blot, pharmacological inhibition of β-catenin, invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pathway epistasis via pharmacological inhibition, microarray and biochemical confirmation; single lab\",\n      \"pmids\": [\"26544896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GRP78 chaperones LRP6, promoting its maturation; knockdown of GRP78 leads to LRP6 misfolding and ERAD-dependent degradation, reducing mature LRP6 levels and thereby suppressing Wnt/HOXB9 signaling and HCC invasion/metastasis. HOXB9 overexpression rescues invasion/metastasis upon GRP78 knockdown.\",\n      \"method\": \"Knockdown (GRP78), overexpression (HOXB9), Western blot, co-immunoprecipitation, invasion/metastasis assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — epistasis rescue experiment with knockdown/overexpression, molecular mechanism via LRP6 maturation proposed and supported; single lab\",\n      \"pmids\": [\"31310747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The hexapeptide motif of HOXB9 acts as a negative regulatory element ('brake') on its MET-inducing and tumor-suppressive activity in gastric carcinoma; a HOXB9 mutant lacking the hexapeptide motif shows more potent MET induction and tumor suppression than wild-type HOXB9.\",\n      \"method\": \"Site-directed mutagenesis (hexapeptide motif deletion), overexpression in gastric cancer cell lines, migration/invasion assays, in vivo xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with functional readout in vitro and in vivo; single lab\",\n      \"pmids\": [\"26536658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HOXB9-dependent expression of MMP9 in NSCLC cells leads to reduced expression of junctional proteins in vascular endothelial cells and enhanced transmigration of tumor cells through an in vitro blood-brain barrier model, establishing a mechanism for HOXB9-driven brain metastasis.\",\n      \"method\": \"In vitro BBB model (endothelial monolayer), shRNA knockdown and overexpression of HOXB9, measurement of junctional proteins, transmigration assay, in vivo brain metastasis in mice\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro BBB functional model with knockdown/overexpression, MMP9 identified as mechanistic intermediate; single lab\",\n      \"pmids\": [\"33411683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HOXB9 interacts with PBX2 to form a heterodimer that transcriptionally upregulates CDK6, promoting G1-to-S phase cell cycle progression and gastric cancer cell division; HOXB9 depletion causes G1 arrest that is phenocopied by CDK6 knockdown, and CDK6 knockdown reverses HOXB9-driven tumor growth.\",\n      \"method\": \"Co-immunoprecipitation (HOXB9-PBX2), ChIP, luciferase reporter assay, shRNA knockdown, cell cycle analysis, xenograft mouse model\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifies HOXB9-PBX2 complex, ChIP and luciferase confirm CDK6 as direct target, epistasis rescue with CDK6 KD, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"37272544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HOXB9 expression is triggered by amino acid deprivation via activating transcription factor 4 (ATF4) in activated T cells; HOXB9 in turn suppresses NF-κB, NFAT, and AP-1 activities, attenuating selective cytokine production in response to amino acid starvation.\",\n      \"method\": \"siRNA knockdown, overexpression, reporter assays for NF-κB/NFAT/AP-1, amino acid deprivation experiments\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional assays without direct binding evidence for HOXB9 on NF-κB/NFAT targets; ATF4 regulation inferred\",\n      \"pmids\": [\"26926958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HOXB9 directly binds to the promoter of SLC7A11 and transcriptionally upregulates its expression; cold atmospheric plasma (CAP) promotes HOXB9 interaction with PCAF, enhancing HOXB9 acetylation, which affects its ubiquitination and protein stability, ultimately downregulating HOXB9/SLC7A11 and promoting ferroptosis in lung cancer cells.\",\n      \"method\": \"Luciferase assay, ChIP, co-immunoprecipitation (HOXB9-PCAF), ubiquitination assay, overexpression/knockdown, in vivo xenograft\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct HOXB9-SLC7A11 promoter binding, PCAF interaction confirmed by Co-IP, in vivo validation; single lab\",\n      \"pmids\": [\"39127016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM11 acts as an E3 ubiquitin ligase that ubiquitinates HOXB9, promoting its degradation and reversing HOXB9-induced NF-κB pathway activation; simultaneous downregulation of TRIM11 and HOXB9 balances inflammation and apoptosis responses in LPS-stimulated THP-1 cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, Western blot, flow cytometry, ELISA\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ubiquitination interaction supported by Co-IP and functional assays, TRIM11 identified as E3 ligase for HOXB9; single lab\",\n      \"pmids\": [\"39903348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Dynamic subcellular localization of HOXB9 protein was characterized during mammalian early embryonic development by immunofluorescence: HOXB9 is mainly nuclear from immature oocyte to blastocyst stage in both mouse and bovine, with trophoblastic cells showing strong nuclear staining while inner cell mass/epiblast cells show dynamic variation in localization including cytoplasmic pools, and HOXB9 is detected in apical vacuoles of mouse visceral endoderm cells.\",\n      \"method\": \"Immunofluorescence microscopy across developmental stages (mouse and bovine), subcellular localization analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — systematic immunofluorescence across developmental stages in two species, conserved pattern; no functional consequence directly established\",\n      \"pmids\": [\"27798681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HOXB9 directly binds the SDC4 promoter (site 2) and activates SDC4 transcription, as confirmed by ChIP and dual-luciferase reporter assay. HOXB9 overexpression promotes SDC4 expression and PKCα activation, leading to reduced tight junction proteins and BBB disruption under ischemic conditions.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, overexpression, TEER assay, immunofluorescence, in vivo MCAO rat model\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP and luciferase confirm HOXB9-SDC4 promoter binding, in vivo validation included; single lab\",\n      \"pmids\": [\"40571266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HOXB9 directly binds the promoter of MMP12 and transcriptionally activates it in laryngeal squamous cell carcinoma; CRISPR/Cas9 knockout of HOXB9 suppresses cell proliferation, migration, invasion and reduces MMP12 expression.\",\n      \"method\": \"CRISPR/Cas9 knockout, ChIP, dual-luciferase reporter assay, microarray, Western blot, immunohistochemistry, in vivo xenograft\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct HOXB9-MMP12 promoter binding, CRISPR knockout with functional readout; single lab\",\n      \"pmids\": [\"38632141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HOXB9 directly binds the SPP1 promoter and transcriptionally upregulates SPP1 expression, protecting osteosarcoma cells from death under glucose starvation conditions.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, overexpression/knockdown, cell viability assay under glucose deprivation\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and luciferase confirm promoter binding, but study is single lab with limited mechanistic depth\",\n      \"pmids\": [\"38621423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IGF2BP3 binds and stabilizes HOXB9 mRNA in an m6A-dependent manner, increasing HOXB9 protein levels; HOXB9 then transcriptionally activates IL15RA expression, and IL-15/IL15RA signaling promotes migration, invasion, and in vivo metastasis of TNBC cells.\",\n      \"method\": \"RNA immunoprecipitation (RIP), Western blot, m6A assay, overexpression/knockdown, in vivo metastasis model\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP confirms IGF2BP3-HOXB9 mRNA binding, m6A dependence shown, downstream IL15RA pathway functionally validated; single lab\",\n      \"pmids\": [\"42168464\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOXB9 is a homeodomain transcription factor that directly binds target gene promoters (including JMJD6, RBL2, E2F3, CDK6 via PBX2 heterodimer, miR-765, MMP12, SLC7A11, SPP1, IL15RA, SDC4) to regulate embryonic patterning, mammary gland development, and cancer progression; its activity is modulated by post-translational modifications—acetylation at K27 by PCAF (reversed by SIRT1) shifts HOXB9 from nucleus to cytoplasm and suppresses oncogenic targets, while AMPKα-mediated phosphorylation at T133 triggers Praja2 E3 ligase-dependent proteasomal degradation and TRIM11 promotes its ubiquitination—and its transcription is activated by WNT/TCF, E2F1, estrogen receptors with MLL1/MLL3, and ERK5 (via BMI1 repression), and enhanced by BTG1/BTG2 co-factors that stabilize its DNA binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HOXB9 is a homeodomain transcription factor that specifies positional and skeletal identity during development and is repeatedly co-opted as a driver of cancer invasion and metastasis [#1, #4, #5]. In the embryo it acts together with paralogous Hox9 genes: loss of Hoxb9 disrupts rib and sternum morphogenesis with synergistic defects in Hoxa9 double mutants [#1], and Hoxa9/Hoxb9/Hoxd9 triple mutants fail in pregnancy-induced mammary ductal expansion [#2], consistent with HOXB9's intrinsic capacity to specify intermediate antero-posterior identity when expressed heterologously [#3]. Its transcriptional output depends on the homeodomain for promoter occupancy [#12] and is enhanced by the BTG1/BTG2 co-factors, which bind HOXB9 and stabilize its DNA binding through its N-terminal activation domain [#0]; in gastric cancer HOXB9 partners with PBX2 to form a heterodimer that activates CDK6 and drives G1-to-S progression [#24]. Across multiple tumor types HOXB9 directly binds and activates target promoters to promote proliferation, EMT, angiogenesis, and metastasis, including JMJD6 [#6], E2F3 [#17], miR-765 [#16], MMP12 [#30], SLC7A11 [#26], SDC4 [#29], and IL15RA [#32], and induces angiogenic and ErbB-ligand programs [#5]; conversely it can act as a tumor suppressor by binding the RBL2 promoter to enforce G0/G1 arrest [#19]. HOXB9 abundance, localization, and activity are tightly controlled by post-translational modification: PCAF acetylates HOXB9 at K27 (reversed by SIRT1), driving nuclear-to-cytoplasmic relocation that suppresses oncogenic targets such as JMJD6 and EZH2 [#6, #7], while AMPKα phosphorylation at T133 licenses Praja2-mediated ubiquitination and proteasomal degradation that limits KRAS induction [#18], and TRIM11 ubiquitinates HOXB9 to reverse its NF-\\u03baB-activating activity [#27]. HOXB9 transcription is itself a convergence point for WNT/\\u03b2-catenin/TCF [#4, #20], E2F1 [#13], estrogen-receptor/MLL signaling [#8], and an ERK5\\u2013BMI1 axis [#10], and its mRNA is stabilized by IGF2BP3 in an m6A-dependent manner [#32].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that mammalian HOXB9 is a bona fide positional-identity selector by showing it can impose homeotic transformations in a heterologous organism.\",\n      \"evidence\": \"Heat-shock-driven mouse HoxB9 expression in transgenic Drosophila scoring homeotic transformations\",\n      \"pmids\": [\"8105876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterologous system does not define endogenous mammalian targets\", \"No molecular partners or DNA targets identified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined HOXB9's endogenous developmental role and its functional cooperativity with a paralog by genetic loss-of-function.\",\n      \"evidence\": \"Targeted disruption of hoxb-9 in mice with hoxa-9 double-mutant epistasis analysis of rib/sternum phenotypes\",\n      \"pmids\": [\"9013929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of paralog synergy not resolved\", \"Direct target genes in skeletal patterning unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Extended HOXB9 function beyond skeletal patterning to organ morphogenesis, showing redundancy across Hox9 paralogs in mammary development.\",\n      \"evidence\": \"Hoxa9/Hoxb9/Hoxd9 triple-mutant mice with histological mammary gland analysis\",\n      \"pmids\": [\"9892669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not separate HOXB9-specific from shared paralog contributions\", \"Downstream effectors in ductal expansion not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Provided the first direct biochemical mechanism for HOXB9 transactivation by identifying co-factors that enhance its DNA binding.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, EMSA, and reporter assays defining BTG1/BTG2 interaction and N-terminal activation domain dependence\",\n      \"pmids\": [\"10617598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological target genes co-regulated by BTG proteins not defined\", \"Structural basis of binding enhancement unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed HOXB9 transcription within an upstream signaling hierarchy in lymphoma and linked it to proliferation/apoptosis.\",\n      \"evidence\": \"Expression profiling and knockdown/overexpression mapping an ERK5\\u2013BMI1\\u2013E2F3A axis controlling HOXB9 in Hodgkin lymphoma cells\",\n      \"pmids\": [\"17148583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding of E2F3A/BMI1 to HOXB9 promoter shown\", \"HOXB9 effector targets in this context not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified HOXB9 as a metastasis-driving WNT/TCF effector and characterized its angiogenic/EMT transcriptional program.\",\n      \"evidence\": \"WNT/TCF target identification with shRNA knockdown and in vivo brain/bone metastasis assays; overexpression with xenograft metastasis and target-gene profiling\",\n      \"pmids\": [\"19576624\", \"20080567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct promoter occupancy on individual angiogenic targets not established here\", \"Mechanism distinguishing primary growth from metastasis incomplete\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated the homeodomain is required for HOXB9 promoter occupancy and oncogenic transformation activity.\",\n      \"evidence\": \"ChIP, reporter assays, homeodomain mutagenesis, and soft-agar colony formation\",\n      \"pmids\": [\"22863320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Co-factor requirements for site selection not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined hormone-responsive transcriptional control of HOXB9 by estrogen receptors and chromatin-modifying co-regulators.\",\n      \"evidence\": \"Reporter assays, ChIP, and siRNA showing ER\\u03b1/ER\\u03b2 and MLL1/MLL3 binding to HOXB9 promoter EREs (extended to BPA/CBP-P300 in 2016)\",\n      \"pmids\": [\"21428455\", \"27182052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"In vivo physiological relevance of ER-driven HOXB9 in normal tissue limited\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified E2F1 and CDK4/6 signaling as direct upstream activators of HOXB9 transcription in breast cancer.\",\n      \"evidence\": \"EMSA, ChIP, promoter mutation, and dual-luciferase mapping E2F1 binding at \\u2013404/\\u2013392\",\n      \"pmids\": [\"25136922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Generalizability beyond breast cancer untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established acetylation as a master switch governing HOXB9 oncogenic versus suppressive output by defining its writer, eraser, and site.\",\n      \"evidence\": \"In vitro/in vivo acetylation assays, K27 mutagenesis, PCAF/SIRT1 identification, ChIP on JMJD6, and xenograft (extended in 2018 to nuclear-cytoplasmic relocation and EZH2)\",\n      \"pmids\": [\"27613418\", \"29654889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear export machinery responding to AcK27 not identified\", \"Determinants selecting which targets are switched off unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped multiple upstream pathways and an intramolecular brake controlling HOXB9 activity across cancer types.\",\n      \"evidence\": \"Pathway epistasis for GalNAc-T14/WNT/\\u03b2-catenin and TGF\\u03b21/Kindlin-2 axes; hexapeptide-deletion mutagenesis defining a negative regulatory motif in gastric cancer\",\n      \"pmids\": [\"26544896\", \"25724625\", \"26536658\", \"25081022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependence of oncogenic vs suppressive HOXB9 not mechanistically unified\", \"Some links rely on single-method functional assays\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded the direct HOXB9 target repertoire to non-coding and proliferative effectors driving stemness and migration.\",\n      \"evidence\": \"ChIP and luciferase validating direct binding to miR-765 and E2F3 promoters with knockdown/rescue and xenografts\",\n      \"pmids\": [\"29408459\", \"29724991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab per target\", \"Cross-tumor conservation of these targets untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a phosphodegron controlling HOXB9 stability and identified its kinase and E3 ligase, linking metabolic signaling to HOXB9-driven KRAS expression.\",\n      \"evidence\": \"In vitro kinase assay, T133A mutagenesis, co-IP, AMPK\\u03b1/Praja2 identification, KRAS target validation, and xenograft (RBL2 cell-cycle target defined same year)\",\n      \"pmids\": [\"36001969\", \"35182659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of AMPK\\u2013Praja2 coupling unresolved\", \"How phosphorylation/acetylation switches are integrated unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified PBX2 as a direct heterodimerization partner that channels HOXB9 to a CDK6-driven proliferation program.\",\n      \"evidence\": \"Reciprocal co-IP, ChIP, luciferase on CDK6, knockdown with CDK6 epistasis rescue, and xenograft in gastric cancer\",\n      \"pmids\": [\"37272544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PBX2 partnership generalizes to other HOXB9 targets unknown\", \"Structural basis of the heterodimer not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected HOXB9 to redox/ferroptosis and barrier-disruption programs and refined PTM control of its stability.\",\n      \"evidence\": \"ChIP/luciferase on SLC7A11, MMP12, SPP1, and SDC4 promoters; CAP-induced PCAF-HOXB9 acetylation and ubiquitination assays; in vivo barrier and xenograft models\",\n      \"pmids\": [\"39127016\", \"38632141\", \"38621423\", \"40571266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab per target\", \"Interplay between acetylation and ubiquitination on stability not fully resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Added post-transcriptional m6A control of HOXB9 abundance feeding an IL-15 signaling axis in metastasis.\",\n      \"evidence\": \"RIP, m6A assays, and metastasis models showing IGF2BP3 stabilizes HOXB9 mRNA driving IL15RA transcription\",\n      \"pmids\": [\"42168464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relative contribution of mRNA vs protein-level control to HOXB9 levels unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HOXB9 selects between oncogenic and tumor-suppressive transcriptional programs across tissues, and how its competing acetylation, phosphorylation, ubiquitination, and m6A controls are integrated in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking PTM state to target-gene selection\", \"Structural basis of HOXB9 cofactor (BTG, PBX2) complexes undefined\", \"Genome-wide direct binding landscape not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 6, 12, 16, 17, 19, 24, 26, 29, 30, 32]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 12, 13, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 7, 28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 12, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 18, 24]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [19, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 20, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BTG1\", \"BTG2\", \"PBX2\", \"PCAF\", \"SIRT1\", \"Praja2\", \"TRIM11\", \"IGF2BP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}