{"gene":"HOXB9","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"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; triple knockout mice cannot raise pups due to mammary gland hypoplasia after pregnancy, demonstrating a direct functional role in adult mammary development.","method":"Targeted gene disruption (loss-of-function) in mice with specific phenotypic readout (mammary gland hypoplasia post-pregnancy)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, replicated across three paralog knockouts with compound mutant analysis","pmids":["9892669"],"is_preprint":false},{"year":1997,"finding":"Targeted disruption of hoxb-9 causes defects in first and second rib development and sternal abnormalities; compound hoxa-9/hoxb-9 double knockouts show synergistic, more severe thoracic skeletal defects, demonstrating genetic interaction between paralogous Hox genes in thoracic skeletal specification.","method":"Targeted gene disruption (loss-of-function) and genetic epistasis via double-mutant intercross","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined skeletal phenotype plus genetic epistasis with paralog","pmids":["9013929"],"is_preprint":false},{"year":2009,"finding":"HOXB9, a WNT/TCF target gene, mediates chemotactic invasion and colony outgrowth of lung adenocarcinoma cells and enhances competence to colonize bone and brain; reduction of HOXB9 attenuates brain and bone metastasis in mice independently of primary lung tumor growth.","method":"Gain-of-function/loss-of-function (shRNA knockdown, overexpression) in metastatic lung adenocarcinoma cell lines and mouse metastasis models","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays (in vitro invasion, in vivo metastasis) replicated in independent cell lines, published in high-impact journal","pmids":["19576624"],"is_preprint":false},{"year":2009,"finding":"HOXB9 is a transcription factor that induces expression of multiple angiogenic factors (VEGF, bFGF, IL-8, ANGPTL-2) and ErbB ligands (amphiregulin, epiregulin, neuregulins) as well as TGF-β, leading to increased cell motility and acquisition of mesenchymal phenotypes; in vivo, HOXB9 promotes formation of well-vascularized tumors that metastasize to the lung.","method":"Overexpression in breast cancer cells, in vitro motility assays, in vivo xenograft and metastasis models, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (gene expression, in vitro, in vivo), replicated across several readouts","pmids":["20080567"],"is_preprint":false},{"year":2000,"finding":"BTG1 and BTG2 physically interact with HOXB9 homeodomain protein (identified by yeast two-hybrid screening), enhance HOXB9-mediated transcription in transfected cells, form a complex on HOXB9-responsive DNA targets, and facilitate HOXB9 binding to DNA; the transcriptional activity depends on the N-terminal activation domain of HOXB9.","method":"Yeast two-hybrid screening, co-immunoprecipitation, DNA-binding assay, transfection reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction confirmed by multiple methods (Y2H, Co-IP, reporter, DNA-binding assay)","pmids":["10617598"],"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 can be reversed by deacetylase SIRT1. AcK27-HOXB9 suppresses transcription of target gene JMJD6 by occupying its promoter, and decreases cancer cell migration and tumor growth compared to wild-type HOXB9.","method":"Co-immunoprecipitation, in vitro acetylation assay, site-directed mutagenesis (K27), ChIP assay, functional cell migration and xenograft assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — in vitro acetylation assay plus mutagenesis plus ChIP plus functional validation","pmids":["27613418"],"is_preprint":false},{"year":2018,"finding":"AcK27-HOXB9 translocates from the nucleus to the cytoplasm, suppressing transcription of oncogenic EZH2, whereas non-acetylated HOXB9 remains nuclear and promotes EZH2 expression and colon cancer progression; subcellular fractionation and immunofluorescence confirmed nucleocytoplasmic translocation.","method":"Subcellular fractionation, immunofluorescence, luciferase reporter assay, site-directed mutagenesis","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1-2 — direct localization experiment tied to functional consequence (EZH2 transcription suppression), with mutagenesis validation","pmids":["29654889"],"is_preprint":false},{"year":2022,"finding":"AMPKα phosphorylates HOXB9 at threonine 133 (T133), promoting E3 ligase Praja2-mediated HOXB9 ubiquitination and degradation; blocking HOXB9 phosphorylation (AMPKα1/2 depletion or HOXB9-T133A mutant) stabilizes HOXB9, upregulates KRAS (identified as a direct HOXB9 transcriptional target), and promotes tumor growth.","method":"Phosphorylation assay, site-directed mutagenesis (T133A), ubiquitination assay, ChIP, cell and xenograft models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — in vitro phosphorylation, mutagenesis, ubiquitination assay, ChIP, functional in vivo validation","pmids":["36001969"],"is_preprint":false},{"year":2012,"finding":"HOXB9 binds directly to promoters of tumor growth and angiogenic factors (via its homeodomain) and regulates their expression; the homeodomain is required for transcriptional regulation of these factors and for 3D colony formation in soft agar, indicating a functional role in tumorigenesis.","method":"ChIP assay, homeodomain deletion mutant analysis, soft agar colony formation assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and domain-deletion with functional readout, single lab","pmids":["22863320"],"is_preprint":false},{"year":2011,"finding":"HOXB9 is transcriptionally regulated by estrogen (E2) via estrogen-response elements (EREs) in its promoter; estrogen receptors ERα and ERβ and histone methylases MLL1 and MLL3 bind to HOXB9 EREs in an E2-dependent manner and are required for E2-mediated HOXB9 transcriptional activation.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), ERE mutational analysis","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus reporter assay with mutational analysis, single lab","pmids":["21428455"],"is_preprint":false},{"year":2016,"finding":"BPA (bisphenol-A) induces HOXB9 expression via EREs in the HOXB9 promoter, requiring estrogen receptors and chromatin modification factors (MLL histone methylase, CBP/P300 acetylases) that bind to HOXB9 EREs in the presence of BPA, leading to histone methylation and acetylation and gene activation.","method":"Luciferase reporter assay, ChIP, ERE mutational analysis, in vivo animal (OVX rat) model","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus luciferase plus in vivo, single lab","pmids":["27182052"],"is_preprint":false},{"year":2008,"finding":"The Hoxb9 promoter forms secondary DNA structures that regulate promoter activity; FBXL10 (KDM2B) was isolated as a protein that specifically binds these secondary-structured promoter DNA sequences and affects Hoxb9 promoter activity.","method":"DNA secondary structure analysis, promoter-activity reporter assay, protein isolation/pulldown from nuclear extracts","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional promoter assay with specific binding protein identification, single lab","pmids":["18276649"],"is_preprint":false},{"year":2016,"finding":"miR-192 suppresses HOXB9 (and EGR1) expression, thereby globally downregulating angiogenic pathways in cancer cells; HOXB9 is identified as a central downstream effector of miR-192's anti-angiogenic function.","method":"miRNA overexpression/inhibition in vitro and in vivo, gene expression analysis, in vivo DOPC nanoliposome delivery","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — functional in vitro and in vivo experiments with multiple tumor models, though HOXB9 mechanistic role is downstream inference","pmids":["27041221"],"is_preprint":false},{"year":2014,"finding":"HOXB9 promotes epithelial-to-mesenchymal transition (EMT) in hepatocellular carcinoma cells through the TGF-β1 pathway; knockdown decreases migration and invasion while overexpression increases these phenotypes.","method":"siRNA knockdown, overexpression, cell migration/invasion assays, EMT marker analysis","journal":"Clinical and experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD/OE with defined cellular phenotype and pathway placement (TGF-β1), single lab","pmids":["25081022"],"is_preprint":false},{"year":2014,"finding":"HOXB9 promotes mesenchymal-to-epithelial transition (MET) in colon adenocarcinoma cells by downregulating EMT-promoting transcription factors (Snail, Twist, FOXC2, ZEB1) and upregulating epithelial proteins (E-cadherin, claudins, occludin, ZO-1); overexpression inhibits colon cancer cell growth, migration, invasion, and metastasis in vivo.","method":"Overexpression/knockdown, RNA sequencing, in vitro cell assays, in vivo xenograft/metastasis model","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays in vitro and in vivo with transcriptome profiling, single lab","pmids":["25025961"],"is_preprint":false},{"year":2015,"finding":"HOXB9 hexapeptide motif acts as a 'brake' on its own MET induction and tumor suppression activity in gastric carcinoma; a HOXB9 mutant lacking the hexapeptide motif showed more potent MET induction and tumor suppression than wild-type HOXB9.","method":"Domain deletion/mutant analysis, cell proliferation/migration/invasion assays, structural analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — domain-deletion mutagenesis with functional readout, single lab","pmids":["26536658"],"is_preprint":false},{"year":2018,"finding":"E2F1 directly binds the HOXB9 promoter region (-404 to -392) and transcriptionally activates HOXB9 in breast cancer cells; confirmed by EMSA, ChIP, and mutational analysis of the binding site.","method":"Dual luciferase reporter assay, EMSA, ChIP, mutational analysis, Q-PCR in multiple cell lines","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (EMSA, ChIP, mutagenesis, reporter), single lab","pmids":["25136922"],"is_preprint":false},{"year":2019,"finding":"GRP78 regulates HOXB9 expression through the Wnt signaling pathway by chaperoning LRP6; GRP78 promotes LRP6 maturation, and knockdown of GRP78 leads to LRP6 misfolding and ERAD degradation, reducing mature LRP6 and suppressing Wnt/HOXB9 signaling, thereby decreasing HCC invasion and metastasis.","method":"GRP78 knockdown, Wnt pathway inhibition, LRP6 maturation assay, rescue experiments with HOXB9 overexpression","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway epistasis established by rescue experiments with multiple knockdowns, single lab","pmids":["31310747"],"is_preprint":false},{"year":2022,"finding":"HOXB9 blocks cell cycle progression at G0/G1 in pancreatic cancer cells by transcriptionally upregulating RBL2 and inhibiting c-Myc; DNMT1 suppresses HOXB9 expression in pancreatic cancer by promoting methylation of the HOXB9 promoter; the DNMT1/HOXB9/RBL2/c-Myc axis regulates pancreatic cancer cell proliferation.","method":"Cell cycle PCR array, flow cytometry, ChIP-qPCR, luciferase assay, promoter methylation analysis, xenograft models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing pathway position and mechanism, single lab","pmids":["35182659"],"is_preprint":false},{"year":2023,"finding":"HOXB9 interacts with PBX2 to form a heterodimer that transcriptionally upregulates CDK6; E2F1 activates HOXB9 expression upstream; depletion of HOXB9 causes G1-phase cell cycle arrest by downregulating CDK6 and a subset of cell cycle genes in gastric cancer cells.","method":"Co-immunoprecipitation, ChIP, reporter assay, siRNA knockdown, flow cytometry (cell cycle), CDK6 inhibitor rescue","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP demonstrating HOXB9-PBX2 complex, ChIP showing CDK6 promoter occupancy, functional rescue, single lab","pmids":["37272544"],"is_preprint":false},{"year":2018,"finding":"HOXB9 directly binds the promoter of microRNA-765 and facilitates its transcription, which in turn targets FOXA2; this HOXB9-miR-765-FOXA2 axis promotes cancer stem cell self-renewal and ER stress resistance in melanoma.","method":"ChIP assay, luciferase reporter, miRNA target validation, cancer stem cell assays","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP and reporter confirming direct promoter binding, single lab","pmids":["29408459"],"is_preprint":false},{"year":2016,"finding":"HOXB9 is expressed in mammalian oocytes and early embryos; its protein distribution is dynamic, mainly nuclear, with strong nuclear staining in trophoblastic cells, while epiblast cells progressively downregulate HOXB9 after blastocyst stage; presence in apical vacuoles of mouse visceral endoderm cells suggests roles in early embryonic development.","method":"Immunofluorescence localization in mouse and bovine oocytes and early embryos (multiple developmental stages)","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 — localization without direct functional link established","pmids":["27798681"],"is_preprint":false},{"year":2015,"finding":"GalNAc-T14 increases sensitivity of the WNT response and stability of β-catenin protein, leading to induced HOXB9 expression and acquisition of invasive phenotype in lung cancer; pharmacological inhibition of β-catenin suppressed HOXB9 expression and invasion, placing HOXB9 downstream of the GalNAc-T14/WNT/β-catenin axis.","method":"Microarray, biochemical analysis, pharmacological inhibition (β-catenin inhibitor), invasion assays","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 — pathway epistasis established by pharmacological inhibition with modest mechanistic depth, single lab","pmids":["26544896"],"is_preprint":false},{"year":2018,"finding":"HOXB9 promotes E2F3 expression by directly binding to the E2F3 promoter in endometrial cancer cells; E2F3 knockdown abolished HOXB9-enhanced cell migration.","method":"ChIP assay, reporter assay, siRNA knockdown, migration assay","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 — ChIP showing promoter occupancy with functional rescue, single lab, limited mechanistic detail","pmids":["29724991"],"is_preprint":false},{"year":2024,"finding":"CAP (cold atmospheric plasma) promotes HOXB9 interaction with PCAF acetyltransferase, increasing HOXB9 acetylation; acetylated HOXB9 has altered ubiquitination and reduced protein stability. HOXB9 directly targets and regulates SLC7A11 transcription (confirmed by luciferase and ChIP assays); CAP suppresses HOXB9/SLC7A11 axis to enhance ferroptosis in lung cancer cells.","method":"ChIP, luciferase assay, Co-IP, ubiquitination assay, ferroptosis assays, xenograft model","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assays confirming direct SLC7A11 promoter binding, plus PCAF interaction and ubiquitination assays, single lab","pmids":["39127016"],"is_preprint":false},{"year":2020,"finding":"HOXB9-dependent expression of MMP9 in NSCLC cells leads to degradation of intercellular adhesion proteins in BBB endothelial cells and promotes tumor cell transmigration; knockdown and overexpression experiments using an in vitro BBB model confirmed this mechanism.","method":"In vitro BBB model, knockdown/overexpression, MMP9 expression analysis, endothelial junctional protein analysis","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 — in vitro BBB model with KD/OE, pathway placement is partial (MMP9 induction), single lab","pmids":["33411683"],"is_preprint":false},{"year":2024,"finding":"HOXB9 directly binds to the promoter of SPP1 and transcriptionally upregulates SPP1 expression, promoting osteosarcoma cell survival and growth under glucose starvation.","method":"ChIP assay, luciferase reporter, functional cell survival and growth assays under glucose starvation","journal":"Biochemical pharmacology","confidence":"Low","confidence_rationale":"Tier 3 — ChIP with functional assay, single lab, limited mechanistic context","pmids":["38621423"],"is_preprint":false},{"year":1993,"finding":"Mouse HoxB9 (Hox-2.5), when expressed in Drosophila under heat shock promoter control, induces homeotic transformations of head toward more posterior identities in larvae and adults, sharing similarities with Abdominal-B phenotypes but also with Antennapedia/HoxB6 transformations, indicating partial functional conservation with Drosophila HOM genes.","method":"Ectopic expression in Drosophila (heat shock promoter), phenotypic analysis of homeotic transformations","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 — direct gain-of-function in Drosophila with defined phenotypic readout, demonstrates functional conservation","pmids":["8105876"],"is_preprint":false},{"year":2007,"finding":"HOXB9 expression in Hodgkin lymphoma is regulated by E2F3A (activator) and BMI1 (repressor); constitutively active ERK5 signaling mediates HOXB9 expression by repressing BMI1. Knockdown and overexpression assays indicated HOXB9 influences both proliferation and apoptosis in HL cells.","method":"RT-PCR, microarray profiling, siRNA knockdown, overexpression, ERK5 pathway analysis","journal":"Blood","confidence":"Low","confidence_rationale":"Tier 3 — pathway epistasis via expression/knockdown analysis, single lab, limited mechanistic depth","pmids":["17148583"],"is_preprint":false},{"year":2000,"finding":"A targeted 90-kb deletion from Hoxb1 to Hoxb9 produces an ordered series of one-segment anterior homeotic transformations along the cervical and thoracic vertebral column; the resulting phenotype is approximately the sum of individual single-gene mutant phenotypes, with no synergistic or novel phenotypes, except loss of ventral curvature at cervicothoracic boundary.","method":"Targeted chromosomal deletion in mice, skeletal analysis, neurofilament staining","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO (cluster deletion) with defined phenotypic readout, genetic epistasis with single-gene mutants","pmids":["10885747"],"is_preprint":false}],"current_model":"HOXB9 is a homeodomain transcription factor that directly binds promoters of target genes (including JMJD6, KRAS, RBL2, EZH2, CDK6, SLC7A11, SPP1, miR-765, angiogenic factors), is regulated by post-translational modifications (PCAF-mediated acetylation at K27 and AMPKα-mediated phosphorylation at T133 that triggers Praja2-mediated degradation), interacts with co-factors BTG1/BTG2 and PBX2, and controls development (mammary gland, thoracic skeleton), cell cycle progression, EMT, angiogenesis, and metastasis, with its nuclear-cytoplasmic localization and transcriptional activity modulated by acetylation state."},"narrative":{"teleology":[{"year":1993,"claim":"Cross-species ectopic expression established that mouse HoxB9 retains homeotic selector function, converting Drosophila head structures toward posterior identities, thereby placing HOXB9 within a functionally conserved HOX framework.","evidence":"Heat-shock–driven expression of mouse HoxB9 in Drosophila, scored for homeotic transformations","pmids":["8105876"],"confidence":"Medium","gaps":["Transformation phenotype partially overlaps Antp and Abd-B classes, so precise paralog-equivalent identity in flies is ambiguous","No DNA-binding target analysis in this system"]},{"year":1997,"claim":"Gene targeting in mice revealed that Hoxb9 is required for normal rib and sternum morphogenesis, and genetic epistasis with Hoxa9 showed synergistic skeletal defects, establishing paralog cooperation in thoracic patterning.","evidence":"Targeted gene disruption in mice and Hoxa9/Hoxb9 double-mutant intercross with skeletal phenotyping","pmids":["9013929"],"confidence":"High","gaps":["Downstream skeletal target genes not identified","Mechanisms of paralog cooperation (shared or distinct targets) unknown"]},{"year":1999,"claim":"Triple-paralog knockout (Hoxa9/Hoxb9/Hoxd9) demonstrated a direct requirement for these Hox genes in pregnancy-induced mammary gland expansion, extending HOXB9 function beyond embryonic skeletal patterning to adult epithelial organogenesis.","evidence":"Compound knockout mice; mammary gland hypoplasia post-pregnancy phenotype","pmids":["9892669"],"confidence":"High","gaps":["Individual contribution of Hoxb9 vs. paralog redundancy in mammary gland not fully resolved","Mammary target genes not identified"]},{"year":2000,"claim":"Identification of BTG1 and BTG2 as HOXB9-interacting cofactors that enhance its DNA binding and transcriptional activity provided the first molecular insight into how HOXB9 assembles productive transcription complexes, with the N-terminal domain required for activation.","evidence":"Yeast two-hybrid, co-immunoprecipitation, DNA-binding assay, and reporter assays","pmids":["10617598"],"confidence":"High","gaps":["Endogenous genomic targets of the HOXB9–BTG complex not mapped","Structural basis of the interaction unknown"]},{"year":2009,"claim":"Two landmark studies established HOXB9 as an activator of angiogenic factors, ErbB ligands, and TGF-β in breast cancer EMT and as a WNT/TCF-responsive driver of organ-specific metastasis in lung adenocarcinoma, repositioning HOXB9 as a cancer-relevant transcription factor.","evidence":"Gain/loss-of-function in breast and lung cancer cell lines; in vivo xenograft, metastasis, and angiogenesis models","pmids":["19576624","20080567"],"confidence":"High","gaps":["Direct versus indirect transcriptional control of individual angiogenic targets not distinguished at this stage","Relative importance of WNT input versus other upstream signals in different tumor types unresolved"]},{"year":2012,"claim":"ChIP and homeodomain-deletion analysis confirmed that HOXB9 directly occupies promoters of angiogenic and growth factor genes through its homeodomain, linking sequence-specific DNA binding to its tumorigenic output.","evidence":"ChIP assay and homeodomain deletion mutant in breast cancer cells with soft-agar colony assay","pmids":["22863320"],"confidence":"Medium","gaps":["Genome-wide binding profile not determined","Cofactor requirements at individual promoters not dissected"]},{"year":2014,"claim":"Context-dependent roles of HOXB9 in epithelial plasticity were revealed: it promotes EMT via TGF-β1 in hepatocellular carcinoma but induces MET by repressing Snail/Twist/ZEB1 in colon adenocarcinoma, indicating tissue-specific transcriptional programs.","evidence":"Knockdown/overexpression, EMT marker analysis, RNA-seq, and in vivo metastasis models in HCC and colon cancer cells","pmids":["25081022","25025961"],"confidence":"Medium","gaps":["Molecular basis for opposing EMT/MET outcomes in different tissues not resolved","Tissue-specific cofactors that redirect HOXB9 activity not identified"]},{"year":2016,"claim":"Discovery that PCAF acetylates HOXB9 at K27 (reversed by SIRT1) introduced the first post-translational switch controlling HOXB9: acetylation suppresses JMJD6 transcription and reduces migration, revealing a regulatory layer beyond expression control.","evidence":"In vitro acetylation assay, site-directed mutagenesis (K27), ChIP, migration and xenograft assays","pmids":["27613418"],"confidence":"High","gaps":["Full spectrum of acetylation-sensitive target genes unknown","Whether other acetyltransferases modify K27 not tested"]},{"year":2018,"claim":"Acetylation at K27 was shown to trigger nucleocytoplasmic translocation of HOXB9, functionally uncoupling it from nuclear targets such as EZH2 and explaining how acetylation suppresses oncogenic transcription.","evidence":"Subcellular fractionation, immunofluorescence, luciferase reporter, and K27 mutagenesis in colon cancer cells","pmids":["29654889"],"confidence":"High","gaps":["Export mechanism (NES, carrier) mediating cytoplasmic translocation not characterized","Potential cytoplasmic functions of acetylated HOXB9 unknown"]},{"year":2022,"claim":"AMPKα phosphorylation of HOXB9 at T133 was identified as a second post-translational switch, triggering Praja2-mediated ubiquitination and degradation; blocking this axis stabilizes HOXB9 and upregulates its direct target KRAS, linking metabolic sensing to HOXB9 protein turnover.","evidence":"Phosphorylation assay, T133A mutagenesis, ubiquitination assay, ChIP at KRAS promoter, xenograft models","pmids":["36001969"],"confidence":"High","gaps":["Other E3 ligases that may target HOXB9 not surveyed","Integration between AMPK-mediated degradation and PCAF-mediated acetylation signals not examined"]},{"year":2023,"claim":"HOXB9 was shown to heterodimerize with PBX2 to co-occupy and activate the CDK6 promoter, directly coupling HOXB9 to G1/S cell-cycle progression and explaining its proliferation-promoting activity in gastric cancer.","evidence":"Co-immunoprecipitation, ChIP, reporter assay, CDK6 inhibitor rescue, and cell-cycle analysis in gastric cancer cells","pmids":["37272544"],"confidence":"Medium","gaps":["Whether PBX2 is required at all HOXB9 target promoters unknown","Structural details of HOXB9-PBX2 heterodimer not available"]},{"year":2024,"claim":"Identification of SLC7A11 as a direct HOXB9 transcriptional target linked HOXB9 to ferroptosis regulation; CAP-enhanced PCAF-mediated acetylation destabilizes HOXB9 and suppresses SLC7A11, revealing convergence of the acetylation and ubiquitination regulatory axes on redox defense.","evidence":"ChIP, luciferase, Co-IP, ubiquitination assay, ferroptosis assays, and xenograft in lung cancer","pmids":["39127016"],"confidence":"Medium","gaps":["Whether HOXB9-driven SLC7A11 regulation occurs outside the CAP treatment context not established","Relative contribution of HOXB9 versus other transcription factors to SLC7A11 expression unclear"]},{"year":null,"claim":"Key unresolved questions include the genome-wide direct target repertoire of HOXB9 (no ChIP-seq available), the structural basis for cofactor selectivity (PBX2, BTG1/2), the mechanism of acetylation-driven nuclear export, and how tissue context dictates opposing EMT vs. MET outputs.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide binding data (ChIP-seq/CUT&RUN) for HOXB9","No structural model of HOXB9 homeodomain with DNA or cofactors","Crosstalk between K27 acetylation and T133 phosphorylation not investigated","Molecular determinants of tissue-specific EMT versus MET outcomes uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,8,19,26]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,5,6,7,8,18,19,24,26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,21]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,5,7,8,18,19,24,26]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,22]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[18,19]}],"complexes":[],"partners":["BTG1","BTG2","PBX2","PCAF","SIRT1","PRKAA1","RNF111"],"other_free_text":[]},"mechanistic_narrative":"HOXB9 is a homeodomain transcription factor that patterns the axial skeleton and mammary gland during development and, in adult tissues, regulates cell proliferation, angiogenesis, epithelial–mesenchymal transitions, and metastatic competence. It binds promoters of diverse target genes—including angiogenic factors (VEGF, bFGF, IL-8), cell-cycle regulators (CDK6, RBL2), oncogenes (KRAS, EZH2), and SLC7A11—often as a heterodimer with cofactors such as PBX2 and BTG1/BTG2 [PMID:19576624, PMID:20080567, PMID:37272544, PMID:10617598, PMID:36001969]. Its transcriptional activity and stability are tuned by post-translational modifications: PCAF-mediated acetylation at K27 triggers nuclear-to-cytoplasmic translocation and attenuates oncogenic target gene expression, while AMPKα-mediated phosphorylation at T133 promotes Praja2-dependent ubiquitination and proteasomal degradation [PMID:27613418, PMID:29654889, PMID:36001969]. Loss-of-function studies in mice demonstrate that Hoxb9 is required for thoracic rib and sternum specification and, together with paralogous Hox genes, for pregnancy-induced mammary epithelial expansion [PMID:9013929, PMID:9892669]."},"prefetch_data":{"uniprot":{"accession":"P17482","full_name":"Homeobox protein Hox-B9","aliases":["Homeobox protein Hox-2.5","Homeobox protein Hox-2E"],"length_aa":250,"mass_kda":28.1,"function":"Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P17482/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HOXB9","classification":"Not Classified","n_dependent_lines":40,"n_total_lines":1208,"dependency_fraction":0.033112582781456956},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HOXB9","total_profiled":1310},"omim":[{"mim_id":"613004","title":"HUNTINGTIN; HTT","url":"https://www.omim.org/entry/613004"},{"mim_id":"608985","title":"RING FINGER PROTEIN 2; RNF2","url":"https://www.omim.org/entry/608985"},{"mim_id":"606265","title":"E1A-BINDING PROTEIN, 400-KD; EP400","url":"https://www.omim.org/entry/606265"},{"mim_id":"604607","title":"HOMEOBOX B13; HOXB13","url":"https://www.omim.org/entry/604607"},{"mim_id":"602842","title":"GEMININ DNA REPLICATION INHIBITOR; GMNN","url":"https://www.omim.org/entry/602842"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34948228","citation_count":12,"is_preprint":false},{"pmid":"33666541","id":"PMC_33666541","title":"miR-557 suppressed the malignant behaviours of osteosarcoma cells by reducing HOXB9 and deactivating the EMT process.","date":"2021","source":"Artificial cells, nanomedicine, and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/33666541","citation_count":12,"is_preprint":false},{"pmid":"33411683","id":"PMC_33411683","title":"HOXB9 enhances the ability of lung cancer cells to penetrate the blood-brain barrier.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33411683","citation_count":12,"is_preprint":false},{"pmid":"18276649","id":"PMC_18276649","title":"Secondary DNA structure formation for Hoxb9 promoter and identification of its specific binding protein.","date":"2008","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/18276649","citation_count":12,"is_preprint":false},{"pmid":"1349742","id":"PMC_1349742","title":"The murine Hox-2.4 promoter contains a functional octamer motif.","date":"1992","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1349742","citation_count":11,"is_preprint":false},{"pmid":"35634239","id":"PMC_35634239","title":"HOXB9 mediates resistance to chemotherapy and patient outcomes through the TGFβ pathway in pancreatic cancer.","date":"2022","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/35634239","citation_count":10,"is_preprint":false},{"pmid":"16051213","id":"PMC_16051213","title":"Ets identified as a trans-regulatory factor of amphioxus Hox2 by transgenic analysis using ascidian embryos.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16051213","citation_count":10,"is_preprint":false},{"pmid":"2907403","id":"PMC_2907403","title":"Restriction fragment length polymorphism and chromosome mapping of a mouse homeo box gene, Hox-2.1.","date":"1988","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2907403","citation_count":10,"is_preprint":false},{"pmid":"26926958","id":"PMC_26926958","title":"HOXB9 acts as a negative regulator of activated human T cells in response to amino acid deficiency.","date":"2016","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26926958","citation_count":10,"is_preprint":false},{"pmid":"36674764","id":"PMC_36674764","title":"HOXB9 Overexpression Confers Chemoresistance to Ovarian Cancer Cells by Inducing ERCC-1, MRP-2, and XIAP.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36674764","citation_count":9,"is_preprint":false},{"pmid":"37031492","id":"PMC_37031492","title":"HOXB9 a miR-122-5p regulated gene, suppressed the anticancer effects of brusatol by upregulating SCD1 expression in melanoma.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/37031492","citation_count":9,"is_preprint":false},{"pmid":"31372881","id":"PMC_31372881","title":"Acetylated HOXB9 at lysine 27 is of differential diagnostic value in patients with pancreatic ductal adenocarcinoma.","date":"2019","source":"Frontiers of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31372881","citation_count":7,"is_preprint":false},{"pmid":"32098919","id":"PMC_32098919","title":"Silencing of HOXB9 suppresses cellular proliferation, angiogenesis, migration and invasion of prostate cancer cells.","date":"2020","source":"Journal of biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/32098919","citation_count":6,"is_preprint":false},{"pmid":"37205792","id":"PMC_37205792","title":"Activation of CTHRC1 by HOXB9 Promotes Angiogenesis through Fatty Acid Metabolism in Lung Adenocarcinoma.","date":"2022","source":"Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion","url":"https://pubmed.ncbi.nlm.nih.gov/37205792","citation_count":6,"is_preprint":false},{"pmid":"38621423","id":"PMC_38621423","title":"HOXB9 promotes osteosarcoma cell survival and malignancy under glucose starvation via upregulating SPP1 expression.","date":"2024","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38621423","citation_count":6,"is_preprint":false},{"pmid":"7890121","id":"PMC_7890121","title":"The 5'-sequence of the murine Hox-b3 (Hox-2.7) gene and its intron contain multiple transcription-regulatory elements.","date":"1994","source":"The International journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7890121","citation_count":6,"is_preprint":false},{"pmid":"1359814","id":"PMC_1359814","title":"Assignment of the HOX2 and HOX3 gene clusters to the bovine chromosome regions 19q17-qter and 5q14-23.","date":"1992","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1359814","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45797,"output_tokens":6720,"usd":0.119096},"stage2":{"model":"claude-opus-4-6","input_tokens":10437,"output_tokens":3226,"usd":0.199252},"total_usd":0.318348,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\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; triple knockout mice cannot raise pups due to mammary gland hypoplasia after pregnancy, demonstrating a direct functional role in adult mammary development.\",\n      \"method\": \"Targeted gene disruption (loss-of-function) in mice with specific phenotypic readout (mammary gland hypoplasia post-pregnancy)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, replicated across three paralog knockouts with compound mutant analysis\",\n      \"pmids\": [\"9892669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Targeted disruption of hoxb-9 causes defects in first and second rib development and sternal abnormalities; compound hoxa-9/hoxb-9 double knockouts show synergistic, more severe thoracic skeletal defects, demonstrating genetic interaction between paralogous Hox genes in thoracic skeletal specification.\",\n      \"method\": \"Targeted gene disruption (loss-of-function) and genetic epistasis via double-mutant intercross\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined skeletal phenotype plus genetic epistasis with paralog\",\n      \"pmids\": [\"9013929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HOXB9, a WNT/TCF target gene, mediates chemotactic invasion and colony outgrowth of lung adenocarcinoma cells and enhances competence to colonize bone and brain; reduction of HOXB9 attenuates brain and bone metastasis in mice independently of primary lung tumor growth.\",\n      \"method\": \"Gain-of-function/loss-of-function (shRNA knockdown, overexpression) in metastatic lung adenocarcinoma cell lines and mouse metastasis models\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays (in vitro invasion, in vivo metastasis) replicated in independent cell lines, published in high-impact journal\",\n      \"pmids\": [\"19576624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HOXB9 is a transcription factor that induces expression of multiple angiogenic factors (VEGF, bFGF, IL-8, ANGPTL-2) and ErbB ligands (amphiregulin, epiregulin, neuregulins) as well as TGF-β, leading to increased cell motility and acquisition of mesenchymal phenotypes; in vivo, HOXB9 promotes formation of well-vascularized tumors that metastasize to the lung.\",\n      \"method\": \"Overexpression in breast cancer cells, in vitro motility assays, in vivo xenograft and metastasis models, 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 — multiple orthogonal methods (gene expression, in vitro, in vivo), replicated across several readouts\",\n      \"pmids\": [\"20080567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"BTG1 and BTG2 physically interact with HOXB9 homeodomain protein (identified by yeast two-hybrid screening), enhance HOXB9-mediated transcription in transfected cells, form a complex on HOXB9-responsive DNA targets, and facilitate HOXB9 binding to DNA; the transcriptional activity depends on the N-terminal activation domain of HOXB9.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, DNA-binding assay, transfection reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmed by multiple methods (Y2H, Co-IP, reporter, DNA-binding assay)\",\n      \"pmids\": [\"10617598\"],\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 can be reversed by deacetylase SIRT1. AcK27-HOXB9 suppresses transcription of target gene JMJD6 by occupying its promoter, and decreases cancer cell migration and tumor growth compared to wild-type HOXB9.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, site-directed mutagenesis (K27), ChIP assay, functional cell migration and xenograft assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro acetylation assay plus mutagenesis plus ChIP plus functional validation\",\n      \"pmids\": [\"27613418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AcK27-HOXB9 translocates from the nucleus to the cytoplasm, suppressing transcription of oncogenic EZH2, whereas non-acetylated HOXB9 remains nuclear and promotes EZH2 expression and colon cancer progression; subcellular fractionation and immunofluorescence confirmed nucleocytoplasmic translocation.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, luciferase reporter assay, site-directed mutagenesis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct localization experiment tied to functional consequence (EZH2 transcription suppression), with mutagenesis validation\",\n      \"pmids\": [\"29654889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AMPKα phosphorylates HOXB9 at threonine 133 (T133), promoting E3 ligase Praja2-mediated HOXB9 ubiquitination and degradation; blocking HOXB9 phosphorylation (AMPKα1/2 depletion or HOXB9-T133A mutant) stabilizes HOXB9, upregulates KRAS (identified as a direct HOXB9 transcriptional target), and promotes tumor growth.\",\n      \"method\": \"Phosphorylation assay, site-directed mutagenesis (T133A), ubiquitination assay, ChIP, cell and xenograft models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation, mutagenesis, ubiquitination assay, ChIP, functional in vivo validation\",\n      \"pmids\": [\"36001969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HOXB9 binds directly to promoters of tumor growth and angiogenic factors (via its homeodomain) and regulates their expression; the homeodomain is required for transcriptional regulation of these factors and for 3D colony formation in soft agar, indicating a functional role in tumorigenesis.\",\n      \"method\": \"ChIP assay, homeodomain deletion mutant analysis, soft agar colony formation assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and domain-deletion with functional readout, single lab\",\n      \"pmids\": [\"22863320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HOXB9 is transcriptionally regulated by estrogen (E2) via estrogen-response elements (EREs) in its promoter; estrogen receptors ERα and ERβ and histone methylases MLL1 and MLL3 bind to HOXB9 EREs in an E2-dependent manner and are required for E2-mediated HOXB9 transcriptional activation.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), ERE mutational analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus reporter assay with mutational analysis, single lab\",\n      \"pmids\": [\"21428455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BPA (bisphenol-A) induces HOXB9 expression via EREs in the HOXB9 promoter, requiring estrogen receptors and chromatin modification factors (MLL histone methylase, CBP/P300 acetylases) that bind to HOXB9 EREs in the presence of BPA, leading to histone methylation and acetylation and gene activation.\",\n      \"method\": \"Luciferase reporter assay, ChIP, ERE mutational analysis, in vivo animal (OVX rat) model\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus luciferase plus in vivo, single lab\",\n      \"pmids\": [\"27182052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The Hoxb9 promoter forms secondary DNA structures that regulate promoter activity; FBXL10 (KDM2B) was isolated as a protein that specifically binds these secondary-structured promoter DNA sequences and affects Hoxb9 promoter activity.\",\n      \"method\": \"DNA secondary structure analysis, promoter-activity reporter assay, protein isolation/pulldown from nuclear extracts\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional promoter assay with specific binding protein identification, single lab\",\n      \"pmids\": [\"18276649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-192 suppresses HOXB9 (and EGR1) expression, thereby globally downregulating angiogenic pathways in cancer cells; HOXB9 is identified as a central downstream effector of miR-192's anti-angiogenic function.\",\n      \"method\": \"miRNA overexpression/inhibition in vitro and in vivo, gene expression analysis, in vivo DOPC nanoliposome delivery\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro and in vivo experiments with multiple tumor models, though HOXB9 mechanistic role is downstream inference\",\n      \"pmids\": [\"27041221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HOXB9 promotes epithelial-to-mesenchymal transition (EMT) in hepatocellular carcinoma cells through the TGF-β1 pathway; knockdown decreases migration and invasion while overexpression increases these phenotypes.\",\n      \"method\": \"siRNA knockdown, overexpression, cell migration/invasion assays, EMT marker analysis\",\n      \"journal\": \"Clinical and experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD/OE with defined cellular phenotype and pathway placement (TGF-β1), single lab\",\n      \"pmids\": [\"25081022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HOXB9 promotes mesenchymal-to-epithelial transition (MET) in colon adenocarcinoma cells by downregulating EMT-promoting transcription factors (Snail, Twist, FOXC2, ZEB1) and upregulating epithelial proteins (E-cadherin, claudins, occludin, ZO-1); overexpression inhibits colon cancer cell growth, migration, invasion, and metastasis in vivo.\",\n      \"method\": \"Overexpression/knockdown, RNA sequencing, in vitro cell assays, in vivo xenograft/metastasis model\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays in vitro and in vivo with transcriptome profiling, single lab\",\n      \"pmids\": [\"25025961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HOXB9 hexapeptide motif acts as a 'brake' on its own MET induction and tumor suppression activity in gastric carcinoma; a HOXB9 mutant lacking the hexapeptide motif showed more potent MET induction and tumor suppression than wild-type HOXB9.\",\n      \"method\": \"Domain deletion/mutant analysis, cell proliferation/migration/invasion assays, structural analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — domain-deletion mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"26536658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"E2F1 directly binds the HOXB9 promoter region (-404 to -392) and transcriptionally activates HOXB9 in breast cancer cells; confirmed by EMSA, ChIP, and mutational analysis of the binding site.\",\n      \"method\": \"Dual luciferase reporter assay, EMSA, ChIP, mutational analysis, Q-PCR in multiple cell lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (EMSA, ChIP, mutagenesis, reporter), single lab\",\n      \"pmids\": [\"25136922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GRP78 regulates HOXB9 expression through the Wnt signaling pathway by chaperoning LRP6; GRP78 promotes LRP6 maturation, and knockdown of GRP78 leads to LRP6 misfolding and ERAD degradation, reducing mature LRP6 and suppressing Wnt/HOXB9 signaling, thereby decreasing HCC invasion and metastasis.\",\n      \"method\": \"GRP78 knockdown, Wnt pathway inhibition, LRP6 maturation assay, rescue experiments with HOXB9 overexpression\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway epistasis established by rescue experiments with multiple knockdowns, single lab\",\n      \"pmids\": [\"31310747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HOXB9 blocks cell cycle progression at G0/G1 in pancreatic cancer cells by transcriptionally upregulating RBL2 and inhibiting c-Myc; DNMT1 suppresses HOXB9 expression in pancreatic cancer by promoting methylation of the HOXB9 promoter; the DNMT1/HOXB9/RBL2/c-Myc axis regulates pancreatic cancer cell proliferation.\",\n      \"method\": \"Cell cycle PCR array, flow cytometry, ChIP-qPCR, luciferase assay, promoter methylation analysis, xenograft models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing pathway position and mechanism, single lab\",\n      \"pmids\": [\"35182659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HOXB9 interacts with PBX2 to form a heterodimer that transcriptionally upregulates CDK6; E2F1 activates HOXB9 expression upstream; depletion of HOXB9 causes G1-phase cell cycle arrest by downregulating CDK6 and a subset of cell cycle genes in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, reporter assay, siRNA knockdown, flow cytometry (cell cycle), CDK6 inhibitor rescue\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP demonstrating HOXB9-PBX2 complex, ChIP showing CDK6 promoter occupancy, functional rescue, single lab\",\n      \"pmids\": [\"37272544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HOXB9 directly binds the promoter of microRNA-765 and facilitates its transcription, which in turn targets FOXA2; this HOXB9-miR-765-FOXA2 axis promotes cancer stem cell self-renewal and ER stress resistance in melanoma.\",\n      \"method\": \"ChIP assay, luciferase reporter, miRNA target validation, cancer stem cell assays\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and reporter confirming direct promoter binding, single lab\",\n      \"pmids\": [\"29408459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HOXB9 is expressed in mammalian oocytes and early embryos; its protein distribution is dynamic, mainly nuclear, with strong nuclear staining in trophoblastic cells, while epiblast cells progressively downregulate HOXB9 after blastocyst stage; presence in apical vacuoles of mouse visceral endoderm cells suggests roles in early embryonic development.\",\n      \"method\": \"Immunofluorescence localization in mouse and bovine oocytes and early embryos (multiple developmental stages)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization without direct functional link established\",\n      \"pmids\": [\"27798681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GalNAc-T14 increases sensitivity of the WNT response and stability of β-catenin protein, leading to induced HOXB9 expression and acquisition of invasive phenotype in lung cancer; pharmacological inhibition of β-catenin suppressed HOXB9 expression and invasion, placing HOXB9 downstream of the GalNAc-T14/WNT/β-catenin axis.\",\n      \"method\": \"Microarray, biochemical analysis, pharmacological inhibition (β-catenin inhibitor), invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway epistasis established by pharmacological inhibition with modest mechanistic depth, single lab\",\n      \"pmids\": [\"26544896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HOXB9 promotes E2F3 expression by directly binding to the E2F3 promoter in endometrial cancer cells; E2F3 knockdown abolished HOXB9-enhanced cell migration.\",\n      \"method\": \"ChIP assay, reporter assay, siRNA knockdown, migration assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ChIP showing promoter occupancy with functional rescue, single lab, limited mechanistic detail\",\n      \"pmids\": [\"29724991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CAP (cold atmospheric plasma) promotes HOXB9 interaction with PCAF acetyltransferase, increasing HOXB9 acetylation; acetylated HOXB9 has altered ubiquitination and reduced protein stability. HOXB9 directly targets and regulates SLC7A11 transcription (confirmed by luciferase and ChIP assays); CAP suppresses HOXB9/SLC7A11 axis to enhance ferroptosis in lung cancer cells.\",\n      \"method\": \"ChIP, luciferase assay, Co-IP, ubiquitination assay, ferroptosis assays, xenograft model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assays confirming direct SLC7A11 promoter binding, plus PCAF interaction and ubiquitination assays, single lab\",\n      \"pmids\": [\"39127016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HOXB9-dependent expression of MMP9 in NSCLC cells leads to degradation of intercellular adhesion proteins in BBB endothelial cells and promotes tumor cell transmigration; knockdown and overexpression experiments using an in vitro BBB model confirmed this mechanism.\",\n      \"method\": \"In vitro BBB model, knockdown/overexpression, MMP9 expression analysis, endothelial junctional protein analysis\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — in vitro BBB model with KD/OE, pathway placement is partial (MMP9 induction), single lab\",\n      \"pmids\": [\"33411683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HOXB9 directly binds to the promoter of SPP1 and transcriptionally upregulates SPP1 expression, promoting osteosarcoma cell survival and growth under glucose starvation.\",\n      \"method\": \"ChIP assay, luciferase reporter, functional cell survival and growth assays under glucose starvation\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ChIP with functional assay, single lab, limited mechanistic context\",\n      \"pmids\": [\"38621423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Mouse HoxB9 (Hox-2.5), when expressed in Drosophila under heat shock promoter control, induces homeotic transformations of head toward more posterior identities in larvae and adults, sharing similarities with Abdominal-B phenotypes but also with Antennapedia/HoxB6 transformations, indicating partial functional conservation with Drosophila HOM genes.\",\n      \"method\": \"Ectopic expression in Drosophila (heat shock promoter), phenotypic analysis of homeotic transformations\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct gain-of-function in Drosophila with defined phenotypic readout, demonstrates functional conservation\",\n      \"pmids\": [\"8105876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOXB9 expression in Hodgkin lymphoma is regulated by E2F3A (activator) and BMI1 (repressor); constitutively active ERK5 signaling mediates HOXB9 expression by repressing BMI1. Knockdown and overexpression assays indicated HOXB9 influences both proliferation and apoptosis in HL cells.\",\n      \"method\": \"RT-PCR, microarray profiling, siRNA knockdown, overexpression, ERK5 pathway analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway epistasis via expression/knockdown analysis, single lab, limited mechanistic depth\",\n      \"pmids\": [\"17148583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A targeted 90-kb deletion from Hoxb1 to Hoxb9 produces an ordered series of one-segment anterior homeotic transformations along the cervical and thoracic vertebral column; the resulting phenotype is approximately the sum of individual single-gene mutant phenotypes, with no synergistic or novel phenotypes, except loss of ventral curvature at cervicothoracic boundary.\",\n      \"method\": \"Targeted chromosomal deletion in mice, skeletal analysis, neurofilament staining\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO (cluster deletion) with defined phenotypic readout, genetic epistasis with single-gene mutants\",\n      \"pmids\": [\"10885747\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOXB9 is a homeodomain transcription factor that directly binds promoters of target genes (including JMJD6, KRAS, RBL2, EZH2, CDK6, SLC7A11, SPP1, miR-765, angiogenic factors), is regulated by post-translational modifications (PCAF-mediated acetylation at K27 and AMPKα-mediated phosphorylation at T133 that triggers Praja2-mediated degradation), interacts with co-factors BTG1/BTG2 and PBX2, and controls development (mammary gland, thoracic skeleton), cell cycle progression, EMT, angiogenesis, and metastasis, with its nuclear-cytoplasmic localization and transcriptional activity modulated by acetylation state.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HOXB9 is a homeodomain transcription factor that patterns the axial skeleton and mammary gland during development and, in adult tissues, regulates cell proliferation, angiogenesis, epithelial–mesenchymal transitions, and metastatic competence. It binds promoters of diverse target genes—including angiogenic factors (VEGF, bFGF, IL-8), cell-cycle regulators (CDK6, RBL2), oncogenes (KRAS, EZH2), and SLC7A11—often as a heterodimer with cofactors such as PBX2 and BTG1/BTG2 [PMID:19576624, PMID:20080567, PMID:37272544, PMID:10617598, PMID:36001969]. Its transcriptional activity and stability are tuned by post-translational modifications: PCAF-mediated acetylation at K27 triggers nuclear-to-cytoplasmic translocation and attenuates oncogenic target gene expression, while AMPKα-mediated phosphorylation at T133 promotes Praja2-dependent ubiquitination and proteasomal degradation [PMID:27613418, PMID:29654889, PMID:36001969]. Loss-of-function studies in mice demonstrate that Hoxb9 is required for thoracic rib and sternum specification and, together with paralogous Hox genes, for pregnancy-induced mammary epithelial expansion [PMID:9013929, PMID:9892669].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Cross-species ectopic expression established that mouse HoxB9 retains homeotic selector function, converting Drosophila head structures toward posterior identities, thereby placing HOXB9 within a functionally conserved HOX framework.\",\n      \"evidence\": \"Heat-shock–driven expression of mouse HoxB9 in Drosophila, scored for homeotic transformations\",\n      \"pmids\": [\"8105876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transformation phenotype partially overlaps Antp and Abd-B classes, so precise paralog-equivalent identity in flies is ambiguous\", \"No DNA-binding target analysis in this system\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Gene targeting in mice revealed that Hoxb9 is required for normal rib and sternum morphogenesis, and genetic epistasis with Hoxa9 showed synergistic skeletal defects, establishing paralog cooperation in thoracic patterning.\",\n      \"evidence\": \"Targeted gene disruption in mice and Hoxa9/Hoxb9 double-mutant intercross with skeletal phenotyping\",\n      \"pmids\": [\"9013929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream skeletal target genes not identified\", \"Mechanisms of paralog cooperation (shared or distinct targets) unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Triple-paralog knockout (Hoxa9/Hoxb9/Hoxd9) demonstrated a direct requirement for these Hox genes in pregnancy-induced mammary gland expansion, extending HOXB9 function beyond embryonic skeletal patterning to adult epithelial organogenesis.\",\n      \"evidence\": \"Compound knockout mice; mammary gland hypoplasia post-pregnancy phenotype\",\n      \"pmids\": [\"9892669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of Hoxb9 vs. paralog redundancy in mammary gland not fully resolved\", \"Mammary target genes not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of BTG1 and BTG2 as HOXB9-interacting cofactors that enhance its DNA binding and transcriptional activity provided the first molecular insight into how HOXB9 assembles productive transcription complexes, with the N-terminal domain required for activation.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, DNA-binding assay, and reporter assays\",\n      \"pmids\": [\"10617598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous genomic targets of the HOXB9–BTG complex not mapped\", \"Structural basis of the interaction unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Two landmark studies established HOXB9 as an activator of angiogenic factors, ErbB ligands, and TGF-β in breast cancer EMT and as a WNT/TCF-responsive driver of organ-specific metastasis in lung adenocarcinoma, repositioning HOXB9 as a cancer-relevant transcription factor.\",\n      \"evidence\": \"Gain/loss-of-function in breast and lung cancer cell lines; in vivo xenograft, metastasis, and angiogenesis models\",\n      \"pmids\": [\"19576624\", \"20080567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect transcriptional control of individual angiogenic targets not distinguished at this stage\", \"Relative importance of WNT input versus other upstream signals in different tumor types unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"ChIP and homeodomain-deletion analysis confirmed that HOXB9 directly occupies promoters of angiogenic and growth factor genes through its homeodomain, linking sequence-specific DNA binding to its tumorigenic output.\",\n      \"evidence\": \"ChIP assay and homeodomain deletion mutant in breast cancer cells with soft-agar colony assay\",\n      \"pmids\": [\"22863320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide binding profile not determined\", \"Cofactor requirements at individual promoters not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Context-dependent roles of HOXB9 in epithelial plasticity were revealed: it promotes EMT via TGF-β1 in hepatocellular carcinoma but induces MET by repressing Snail/Twist/ZEB1 in colon adenocarcinoma, indicating tissue-specific transcriptional programs.\",\n      \"evidence\": \"Knockdown/overexpression, EMT marker analysis, RNA-seq, and in vivo metastasis models in HCC and colon cancer cells\",\n      \"pmids\": [\"25081022\", \"25025961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for opposing EMT/MET outcomes in different tissues not resolved\", \"Tissue-specific cofactors that redirect HOXB9 activity not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that PCAF acetylates HOXB9 at K27 (reversed by SIRT1) introduced the first post-translational switch controlling HOXB9: acetylation suppresses JMJD6 transcription and reduces migration, revealing a regulatory layer beyond expression control.\",\n      \"evidence\": \"In vitro acetylation assay, site-directed mutagenesis (K27), ChIP, migration and xenograft assays\",\n      \"pmids\": [\"27613418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full spectrum of acetylation-sensitive target genes unknown\", \"Whether other acetyltransferases modify K27 not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Acetylation at K27 was shown to trigger nucleocytoplasmic translocation of HOXB9, functionally uncoupling it from nuclear targets such as EZH2 and explaining how acetylation suppresses oncogenic transcription.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, luciferase reporter, and K27 mutagenesis in colon cancer cells\",\n      \"pmids\": [\"29654889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Export mechanism (NES, carrier) mediating cytoplasmic translocation not characterized\", \"Potential cytoplasmic functions of acetylated HOXB9 unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"AMPKα phosphorylation of HOXB9 at T133 was identified as a second post-translational switch, triggering Praja2-mediated ubiquitination and degradation; blocking this axis stabilizes HOXB9 and upregulates its direct target KRAS, linking metabolic sensing to HOXB9 protein turnover.\",\n      \"evidence\": \"Phosphorylation assay, T133A mutagenesis, ubiquitination assay, ChIP at KRAS promoter, xenograft models\",\n      \"pmids\": [\"36001969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other E3 ligases that may target HOXB9 not surveyed\", \"Integration between AMPK-mediated degradation and PCAF-mediated acetylation signals not examined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"HOXB9 was shown to heterodimerize with PBX2 to co-occupy and activate the CDK6 promoter, directly coupling HOXB9 to G1/S cell-cycle progression and explaining its proliferation-promoting activity in gastric cancer.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, reporter assay, CDK6 inhibitor rescue, and cell-cycle analysis in gastric cancer cells\",\n      \"pmids\": [\"37272544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PBX2 is required at all HOXB9 target promoters unknown\", \"Structural details of HOXB9-PBX2 heterodimer not available\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of SLC7A11 as a direct HOXB9 transcriptional target linked HOXB9 to ferroptosis regulation; CAP-enhanced PCAF-mediated acetylation destabilizes HOXB9 and suppresses SLC7A11, revealing convergence of the acetylation and ubiquitination regulatory axes on redox defense.\",\n      \"evidence\": \"ChIP, luciferase, Co-IP, ubiquitination assay, ferroptosis assays, and xenograft in lung cancer\",\n      \"pmids\": [\"39127016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HOXB9-driven SLC7A11 regulation occurs outside the CAP treatment context not established\", \"Relative contribution of HOXB9 versus other transcription factors to SLC7A11 expression unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the genome-wide direct target repertoire of HOXB9 (no ChIP-seq available), the structural basis for cofactor selectivity (PBX2, BTG1/2), the mechanism of acetylation-driven nuclear export, and how tissue context dictates opposing EMT vs. MET outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide binding data (ChIP-seq/CUT&RUN) for HOXB9\", \"No structural model of HOXB9 homeodomain with DNA or cofactors\", \"Crosstalk between K27 acetylation and T133 phosphorylation not investigated\", \"Molecular determinants of tissue-specific EMT versus MET outcomes uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 8, 19, 26]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 5, 6, 7, 8, 18, 19, 24, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 21]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 5, 7, 8, 18, 19, 24, 26]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 22]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [18, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BTG1\", \"BTG2\", \"PBX2\", \"PCAF\", \"SIRT1\", \"PRKAA1\", \"RNF111\"],\n    \"other_free_text\": []\n  }\n}\n```"}