Affinage

EHF

ETS homologous factor · UniProt Q9NZC4

Length
300 aa
Mass
34.9 kDa
Annotated
2026-06-09
79 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EHF (ESE-3) is an epithelium-restricted ETS-family transcription factor that binds high-affinity ETS motifs in target promoters and acts as a context-dependent activator or repressor to maintain epithelial lineage identity and suppress stem-like and EMT programs (PMID:10644770, PMID:11259407, PMID:22505649). In normal epithelia EHF promotes terminal differentiation—driving corneal epithelial fate (PMID:24142692), colonic enterocytic differentiation through a direct physical interaction with CDX1 via its PNT domain (PMID:35606410), salivary ductal differentiation (PMID:36348499), and mammary lobuloalveolar maturation (PMID:38781975)—and genetic deletion of its ETS DNA-binding domain in mice disrupts epidermal and colonic homeostasis and accelerates tumor development (PMID:34180969). As a tumor suppressor it directly represses EMT and stemness drivers (TWIST1, ZEB2, BMI1, POU5F1, Lin28A/B, CXCR4, SOX9/SOX2/OCT4/NANOG) while activating let-7 microRNAs and E-cadherin, thereby restraining invasion, metastasis, and the cancer stem-like compartment (PMID:22505649, PMID:27197175, PMID:27923832, PMID:33674341); it also represses inflammatory genes including IL-6 and CXCL1, limiting STAT3 activation and CXCR2+ neutrophil recruitment that otherwise drive therapy resistance (PMID:27732936, PMID:38492894). EHF expression is induced by inflammatory cytokines via NF-κB (PMID:18475289), by p38/MEK MAPK signaling (PMID:12444029, PMID:17627613), and by androgen receptor binding at its locus (PMID:33414441), and its silencing by promoter CpG methylation in prostate cancer abolishes its pro-apoptotic and differentiation functions (PMID:18037958). EHF activity is further gated by subcellular partitioning: RRAD- and Dclk2-dependent phosphorylation control its nucleocytoplasmic distribution, and only nuclear EHF executes its transcriptional program (PMID:37279586, PMID:38513137). Beyond epithelia, EHF programs immune cells, repressing FcεRI and c-Kit in mast cells downstream of TGF-β/Smad (PMID:26297757) and directly regulating CCR7, CD200, PD-L1, IRF4 and Rel in CCR7hi conventional dendritic cells to bias CD4+ T cell responses (PMID:41730908). EHF cooperates with coactivators (CBP/p300, AJUBA) and core epithelial transcriptional circuitry (ELF3-KLF5-GATA6) to orchestrate its target networks (PMID:17027647, PMID:38799645).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2000 Medium

    Established that EHF/ESE-3 is an epithelium-restricted ETS factor with DNA-binding and transactivation specificity distinct from its paralog ESE-1, defining it as a sequence-specific transcription factor rather than a generic ETS protein.

    Evidence EMSA, reporter transactivation, and promoter binding analysis on the c-MET promoter

    PMID:10644770

    Open questions at the time
    • No genome-wide binding map
    • Tissue-specific cofactors not identified
  2. 2001 Medium

    Showed EHF can act as a context-dependent repressor of Ras/AP-1-driven transcription and is a nuclear protein lost in carcinomas, framing it early as a differentiation-associated, potentially tumor-suppressive factor.

    Evidence Reporter assays with promoter variants plus immunohistochemistry with a new monoclonal antibody

    PMID:11259407

    Open questions at the time
    • Mechanism of activator/repressor switching unresolved
    • No in vivo loss-of-function
  3. 2003 Medium

    Connected EHF expression to upstream MAPK signaling and demonstrated repression of MMP promoters, linking inflammatory signaling input to EHF-mediated transcriptional output.

    Evidence MMP-1/MMP-3 reporter assays and pharmacological MEK/p38 inhibition in 3T3 and bronchial smooth muscle cells (also #2)

    PMID:10527851 PMID:12444029

    Open questions at the time
    • Direct promoter occupancy not shown by ChIP
    • Endogenous MMP regulation not tested
  4. 2007 Medium

    Identified EHF as a p38-induced effector of senescence that directly activates the p16INK4a promoter, providing a growth-suppressive mechanism downstream of stress signaling.

    Evidence Microarray, ectopic expression, recombinant-protein EMSA, p16 reporter assay and SA-β-gal in a single study

    PMID:17627613

    Open questions at the time
    • Senescence role tested only by overexpression
    • Endogenous EHF requirement not addressed
  5. 2008 Medium

    Defined NF-κB as a direct transcriptional inducer of EHF in airway epithelium, establishing cytokine-driven control of EHF expression.

    Evidence Promoter NF-κB site mutagenesis, cytokine stimulation, reporter assays

    PMID:18475289

    Open questions at the time
    • Functional consequence of induced EHF not assayed here
    • Combinatorial regulation with MAPK input unresolved
  6. 2008 High

    Demonstrated epigenetic silencing of EHF by promoter methylation in prostate cancer and its direct pro-apoptotic activation of caspase-3, anchoring EHF as a methylation-silenced tumor suppressor.

    Evidence Bisulfite sequencing, 5-aza reactivation, clonogenic/apoptosis assays, and ChIP of the caspase-3 promoter

    PMID:18037958

    Open questions at the time
    • In vivo tumor suppression not tested in this study
    • Full apoptotic target set undefined
  7. 2012 Medium

    Established the central tumor-suppressive program: EHF directly represses EMT and cancer-stem-cell genes, and its loss confers stem-like, metastatic properties in prostate epithelium.

    Evidence Loss- and gain-of-function with TWIST1/ZEB2/BMI1/POU5F1 readouts, tumor-initiating assays, tissue microarray

    PMID:22505649

    Open questions at the time
    • Direct vs indirect repression of each target not fully resolved
    • Cofactors mediating repression unidentified
  8. 2013 Medium

    Showed via genome-wide binding that EHF executes complementary activating and repressing programs to specify epithelial fate, generalizing its lineage role beyond cancer.

    Evidence ChIP-seq plus loss-of-function in corneal epithelium, with KLF4/KLF5 cooperativity (also intestinal transcytosis epistasis #10)

    PMID:23439650 PMID:24142692

    Open questions at the time
    • Mechanism of activator/repressor selection at each site unknown
    • KLF4/KLF5 interaction not biochemically defined
  9. 2016 High

    Defined EHF as a node suppressing inflammatory and stemness circuits across epithelial cancers by directly repressing IL-6, Lin28A/B and CXCR4 while activating let-7 and E-cadherin, linking transcriptional control to STAT3 signaling and metastasis suppression.

    Evidence ChIP, reporter assays, sphere-formation, IL-6/JAK inhibition, and orthotopic/xenograft models across prostate and pancreatic cancer

    PMID:27197175 PMID:27732936 PMID:27923832

    Open questions at the time
    • Direct vs indirect contributions to E-cadherin regulation across tissues
    • Determinants of EHF loss in primary tumors only partly defined
  10. 2017 High

    Showed in primary human bronchial epithelium that EHF controls inflammation, wound repair and goblet-cell programs (activating SPDEF), extending its differentiation role to airway homeostasis.

    Evidence ChIP-seq and RNA-seq after EHF depletion, wound-closure and chemokine secretion assays in primary HBE cells

    PMID:28461336

    Open questions at the time
    • In vivo airway phenotype not addressed
    • Direct chemokine targets not all enumerated
  11. 2021 High

    In vivo genetic deletion of the EHF ETS domain established that its DNA-binding activity is essential for epidermal and colonic epithelial homeostasis and restrains Apc-driven tumorigenesis, and identified the EHF-CDX1 PNT-domain interaction driving colonic differentiation.

    Evidence Constitutive and conditional Ehf knockout mice, colitis and Apc tumor models, Co-IP, and Ehf/Cdx1 double-knockout (also #25)

    PMID:34180969 PMID:35606410

    Open questions at the time
    • Mechanism coupling differentiation loss to tumor initiation not fully resolved
    • Tissue-specific cofactor partners beyond CDX1 incomplete
  12. 2021 Medium

    Revealed context-dependent and pro-tumorigenic functions of EHF (direct activation of TGF-β1, RUVBL1, HER2/HER3, KRT16) and signaling inputs (AR-driven expression, LMP2A/STAT3 induction), showing its output is wired by tissue and oncogenic context.

    Evidence ChIP, reporter assays, knockdown/overexpression, in vivo growth/metastasis assays across colorectal, thyroid, oral and gastric cancers (#7,#15,#19,#21,#22,#23,#24,#27)

    PMID:21617703 PMID:27517321 PMID:27567379 PMID:30782177 PMID:32372436 PMID:33414441 PMID:33520362 PMID:34014591

    Open questions at the time
    • What determines activator vs repressor and tumor-suppressor vs oncogenic behavior is unresolved
    • Some target findings rest on single reporter/ChIP studies
  13. 2024 Medium

    Defined post-translational and biophysical control of EHF: RRAD and Dclk2 govern its nucleocytoplasmic distribution, and EHF forms nuclear condensates, with only nuclear EHF repressing TERT, inflammatory and caspase genes—coupling localization to its senescence and cell-death programs.

    Evidence Co-IP, phosphorylation assays, subcellular fractionation, condensate imaging, ChIP, telomere and senescence assays, OGD/CCI and PDAC models (#29,#35,#36)

    PMID:37279586 PMID:38513137 PMID:39710057

    Open questions at the time
    • Structural basis of condensate formation undefined
    • Generality of phospho-regulation across tissues untested
  14. 2024 High

    Established EHF as a regulator of the tumor microenvironment and immune programs—repressing CXCL1 to limit CXCR2+ neutrophil-driven therapy resistance, shaping macrophage polarization, and directly programming dendritic and mast cell receptor/immunosuppressive gene expression.

    Evidence ChIP/CUT&TAG, Ehf-knockout and KPC/humanized mice, single-cell and spatial transcriptomics, conditional DC- and mast-cell studies, T-cell polarization assays (#11,#28,#30,#31,#37,#39)

    PMID:26297757 PMID:38492894 PMID:38741887 PMID:38799645 PMID:39971220 PMID:41730908

    Open questions at the time
    • Whether immune phenotypes are epithelial-cell-intrinsic vs immune-cell-intrinsic varies by study
    • Direct vs paracrine target hierarchies incompletely mapped
  15. 2025 Medium

    Implicated EHF as a disease modifier in cystic fibrosis lung epithelium, where its loss enhances CFTR activity and alters basal-cell and hypoxic transcriptional programs.

    Evidence CRISPR knockout in human iPSC-derived lung cells, CFTR electrophysiology, transepithelial resistance, RNA-seq, HIF-1α assays

    PMID:40590703

    Open questions at the time
    • Mechanism linking EHF to CFTR not defined
    • Not validated in patient airway in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular rules that switch EHF between activator and repressor, between tumor-suppressor and oncogenic output, and between epithelial and immune programs remain unresolved.
  • No unified model of cofactor-dependent activator/repressor selection
  • Structural basis of PNT-domain interactions and condensate assembly undefined
  • Determinants of context-specific tumor-suppressive vs oncogenic roles unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 4 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-74160 Gene expression (Transcription) 8 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-8953897 Cellular responses to stimuli 2
Partners
AJUBACBPCDX1DCLK2EP300KLF4KLF5RRAD

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ESE-3/EHF is an ETS transcription factor exclusively expressed in epithelial cells that transactivates the c-MET promoter via three high-affinity ETS binding sites, and binds promoters of glandular epithelium-specific genes; ESE-3 and ESE-1 differ significantly in their ability to transactivate promoters despite similar DNA binding affinity, establishing distinct target gene specificity within the ESE subfamily. Transactivation reporter assays, electrophoretic mobility shift assay (EMSA), promoter binding analysis The Journal of biological chemistry Medium 10644770
2001 EHF/ESE-3 acts as a context-dependent transcriptional repressor of Ras- or phorbol ester-induced transcriptional activation of promoters containing both ETS and AP-1 binding sites; repression is sequence- and context-dependent, requiring high-affinity ESE-3 binding sites combined with AP-1 cis-elements in a specific arrangement. ESE-3 is a nuclear protein expressed exclusively in differentiated epithelial cells and absent in epithelial carcinomas. Transient transfection reporter assays, immunohistochemistry with newly generated monoclonal antibody, nuclear localization confirmed by immunostaining The Journal of biological chemistry Medium 11259407
1999 EHF protein represses ETS-2-induced activity of both stromelysin-1 (MMP-3) and collagenase-1 (MMP-1) promoters, establishing a functional role as a transcriptional repressor of matrix metalloproteinase genes. Transactivation reporter assay Biochemical and biophysical research communications Low 10527851
2002 ESE-3/EHF overexpression in 3T3 cells and human bronchial smooth muscle cells inhibits MMP-1 promoter activity. Cytokine-induced ESE-3 expression in bronchial smooth muscle cells is mediated by MEK1/2 and p38 MAPK signaling pathways, as specific inhibitors (U0126, SB03580) abrogate induction. Reporter assay (MMP-1 promoter), pharmacological inhibition with specific kinase inhibitors, RT-PCR and protein analysis American journal of respiratory cell and molecular biology Medium 12444029
2007 ESE-3/EHF expression is upregulated by p38 MAPK in cellular senescence. Ectopic expression of ESE-3 induces growth retardation, upregulation of p16(INK4a) (but not p21), and increased SA-β-gal activity. Recombinant ESE-3 protein directly binds ETS-binding sequences in the p16(INK4a) promoter and increases its transcriptional activity in reporter assays. Microarray, ectopic expression, reporter assay, EMSA with recombinant protein, SA-β-gal assay Cancer science Medium 17627613
2007 ESE-3/EHF expression is silenced by methylation of an evolutionarily conserved CpG site in its promoter in prostate cancer cells (PC3, DU145); treatment with 5-aza-2'-deoxycytidine restores expression. Re-expression of ESE-3 in prostate cancer cells inhibits clonogenic survival and induces apoptosis by increasing procaspase-3 levels, mediated at the transcriptional level by direct ESE-3 binding to the caspase-3 promoter. Bisulfite sequencing/methylation analysis, 5-aza-2'-deoxycytidine treatment, clonogenic assay, apoptosis assays, chromatin immunoprecipitation (ChIP) of caspase-3 promoter Oncogene High 18037958
2008 ESE-3/EHF expression in airway epithelial cells is upregulated by inflammatory cytokines IL-1β and TNF-α via NF-κB activation; specific NF-κB binding sequences in the ESE-3 promoter are required for cytokine-induced expression. ESE-1 upregulates ESE-3 expression and downregulates its own cytokine-induced expression. Promoter characterization, NF-κB binding site mutagenesis, cytokine stimulation, RT-PCR, reporter assay Cell research Medium 18475289
2011 EHF directly activates transcription of RUVBL1 (an ATPase associated with chromatin-remodeling complexes). RUVBL1 blocks p53-mediated apoptosis by repressing p53 and its target genes: RUVBL1 binds the p53 promoter, interferes with RNF20/hBRE1-mediated histone H2B monoubiquitination, and promotes PAF1-mediated histone H3K9 trimethylation. This EHF→RUVBL1 axis allows colon tumor cells with wild-type p53 to avoid apoptosis. ChIP, promoter reporter assay, histone modification analysis, siRNA knockdown, apoptosis assays EMBO reports High 21617703
2012 ESE3/EHF represses expression of key EMT and cancer stem cell genes including TWIST1, ZEB2, BMI1, and POU5F1 in prostate epithelial cells. Loss of ESE3/EHF induces EMT, stem-like features, and tumor-initiating/metastatic properties; re-expression inhibits stem-like properties and tumorigenic potential. Gene expression analysis, siRNA knockdown, re-expression experiments, tumor-initiating assays, tissue microarray Cancer research Medium 22505649
2013 EHF promotes cornea epithelial fate through complementary gene-activating and gene-repressing activities, with potential interactions with KLF4 and KLF5 in promoting cornea epithelial differentiation. EHF binding sites and direct targets in cornea epithelium were identified by ChIP-seq combined with loss-of-function studies. ChIP-seq, loss-of-function studies (siRNA/KO), transcriptome profiling, comparison across epithelial tissues The Journal of biological chemistry Medium 24142692
2013 EHF expression in intestinal follicle-associated epithelial cells is sufficient to activate HCK-dependent apical-to-basolateral transcytosis of non-opsonized and SIgA-opsonized particles, placing EHF upstream of HCK kinase in regulating antigen sampling at mucosal surfaces. Ectopic expression of EHF in cultured intestinal epithelial cells, transcytosis assays with particles, pharmacological inhibition of HCK The Journal of biological chemistry Medium 23439650
2015 EHF (Ehf) is upregulated by TGF-β/Smad signaling in mouse bone marrow-derived mast cells. Forced expression of Ehf represses transcription of FcεRIα, FcεRIβ, and c-Kit genes by directly binding their promoters, reducing surface FcεRI and c-Kit expression, suppressing FcεRI-mediated degranulation and cytokine production. EHF also decreases mRNA levels of GATA1, GATA2, and Stat5b, contributing to these effects. Forced expression (stable transfection), promoter binding assay (ChIP/EMSA), flow cytometry, degranulation assay, cytokine measurement, TGF-β treatment Journal of immunology High 26297757
2016 ESE3/EHF directly binds and represses promoters of Lin28A and Lin28B genes in normal prostate cells, while also activating transcription and maturation of let-7 microRNAs. Loss of ESE3/EHF in cancer cells upregulates Lin28A/B and downregulates let-7 microRNAs, which is critical for prostate cancer stem cell expansion. ChIP (promoter binding), gene expression analysis, siRNA/shRNA knockdown, sphere formation assay, xenograft tumor model Cancer research High 27197175
2016 ESE3/EHF directly binds a novel ETS binding site in the IL-6 gene promoter to repress its transcription. Loss of ESE3/EHF in prostate epithelial cells activates IL-6, which then stimulates STAT3 activation and expansion of the cancer stem-like compartment; pharmacological inhibition of IL-6/STAT3 with a JAK inhibitor restrained cancer stem cell growth. ChIP (direct promoter binding), luciferase reporter assay, siRNA knockdown, IL-6 inhibition, JAK inhibitor treatment, sphere formation and in vivo self-renewal assays Oncotarget High 27732936
2016 ESE3/EHF inhibits pancreatic cancer (PDAC) metastasis by directly upregulating E-cadherin expression at the transcriptional level; downregulation of ESE3 in PDAC reduces E-cadherin and promotes cell motility, invasiveness, and metastasis in an orthotopic mouse model. Expression knockdown/overexpression, promoter reporter assay, orthotopic mouse model, ChIP (E-cadherin promoter binding) Cancer research High 27923832
2016 EHF transcriptionally regulates HER2 and HER3 (ERBB2 and ERBB3) in thyroid cancer cells, as demonstrated by dual-luciferase reporter and ChIP assays, identifying EHF as a transcription factor for these receptor tyrosine kinases. Dual-luciferase reporter assay, ChIP, siRNA knockdown and ectopic expression, in vitro and in vivo proliferation/invasion assays Oncotarget Medium 27517321
2017 EHF targets in primary human bronchial epithelial (HBE) cells are enriched for genes involved in inflammation and wound repair, as determined by EHF ChIP-seq and RNA-seq after EHF depletion. EHF depletion alters epithelial secretion of a neutrophil chemokine, slows wound closure in HBE cells, and EHF activates expression of SPDEF, which contributes to goblet cell hyperplasia. ChIP-seq, RNA-seq after EHF depletion, wound closure assay, cytokine secretion measurement, siRNA knockdown in primary HBE cells The Journal of biological chemistry High 28461336
2006 ESE-3/EHF regulates expression of death receptor 5 (DR-5/TRAIL-R2) through binding to Ets binding sequences on the DR-5 promoter, with co-factors CBP and p300 involved in ESE-3-mediated DR-5 upregulation. EMSA, luciferase reporter assay, promoter mutation analysis Biochemical and biophysical research communications Low 17027647
2019 EHF gene produces two transcript variants: a long form (EHF-LF, includes exon 1) and a short form (EHF-SF, excludes exon 1). Only EHF-SF abrogates ETS1-mediated activation of the ZEB1 promoter by promoting degradation of ETS1 proteins, thereby inhibiting EMT. A point mutation within the ETS domain of EHF abolishes this function and causes EHF to act as a dominant negative, enhancing metastasis in vivo. Promoter reporter assay, protein degradation assay, in vivo metastasis model, site-directed mutagenesis, expression of isoform variants Oncogenesis Medium 33712555
2019 miR-365-3p targets EHF (demonstrated by miR-365-3p reducing EHF expression to decrease migration/invasion in OSCC cells). EHF functions as a transcription factor for KRT16 (keratin 16). EHF-driven KRT16 expression promotes association of c-Met with β5-integrin, facilitating downstream Src/STAT3/FAK/ERK signaling in oral squamous cell carcinoma cells. miRNA target validation (reporter assay), ectopic expression and siRNA knockdown, confocal colocalization, protein degradation assay (lysosomal pathway), in vitro and in vivo functional experiments Journal of experimental & clinical cancer research Medium 30782177
2021 EHF suppresses pancreatic cancer stemness by directly repressing transcription of CXCR4 (receptor for CXCL12); EHF also has a cell-autonomous role in suppressing stemness by inhibiting transcription of Sox9, Sox2, Oct4 and Nanog. Rosiglitazone suppresses PC stemness by upregulating EHF. ChIP, luciferase reporter assay, sphere formation assay, flow cytometry, in vivo KPC mouse model, anchorage-independent growth assay Gut High 33674341
2021 Loss of EHF promotes neuroendocrine differentiation (NED) in prostate cancer following androgen deprivation therapy (ADT). ADT reduces EHF transcription by relieving AR binding to androgen-responsive elements in the EHF locus. EHF loss promotes expression and enzymatic activity of EZH2, which catalyzes H3K27me3 to repress downstream target genes and drive NED. ChIP (AR binding to EHF locus), EZH2 activity assay, H3K27me3 measurement, EZH2 inhibitor treatment, knockdown/overexpression in cell and mouse models Cell death & disease Medium 33414441
2021 EHF promotes colorectal carcinoma progression by directly upregulating TGF-β1 transcription, thereby activating canonical TGF-β signaling; ChIP and reporter assays confirmed direct EHF binding to the TGF-β1 promoter. ChIP, luciferase reporter assay, overexpression and knockdown, in vitro and in vivo proliferation/invasion assays Cancer science Medium 32372436
2021 EHF directly activates transcription of RUVBL1 and in colon cancer also promotes cancer progression by downregulating EHD2 and transactivating INPP4B as downstream target genes, as shown by ChIP and reporter assays. ChIP, reporter assay, knockdown/overexpression, in vitro and in vivo growth assays American journal of cancer research Low 33520362
2021 EBV protein LMP2A causes upregulation of EHF via phosphorylation of STAT3 in EBV-positive gastric cancer cells. STAT3 knockdown inhibits cellular growth of EBV-positive GC cells, and this inhibition is rescued by EHF overexpression, establishing EHF downstream of the LMP2A/STAT3 axis. RNA-seq, ChIP (active histone marks, H3K4me3/H3K27ac), siRNA knockdown, overexpression rescue assay, immunostaining Cancer science Medium 34014591
2022 EHF physically interacts with CDX1 via its PNT domain, and together they cooperatively drive transcription of the colonic differentiation marker VIL1. Re-expression of EHF and CDX1 in poorly-differentiated CRC cells induces chromatin remodeling, transcriptional reprogramming, and enterocytic differentiation; compound genetic deletion of Ehf and Cdx1 in the mouse colon disrupts normal colonic differentiation and significantly enhances colorectal tumor progression. Co-immunoprecipitation (physical interaction via PNT domain), reporter assay (VIL1 transcription), chromatin remodeling analysis, re-expression in CRC cells, compound mouse knockout (Ehf/Cdx1 double KO) Cell death and differentiation High 35606410
2021 Ehf knockout mice (ETS DNA-binding domain deleted) develop papillomas in facial skin, abscesses in preputial glands/vulvae, corneal ulcers, increased susceptibility to colitis, impaired goblet cell differentiation in the colon, extensive transcriptional reprogramming of colonic epithelium, and enhanced Apc-initiated adenoma development—establishing that the EHF ETS DNA-binding domain is essential for postnatal epidermal and colonic epithelial homeostasis. Genetic knockout mouse model (ETS domain deletion), intestinal-specific conditional knockout, chemically induced colitis, Apc-mutation tumor model, histology, transcriptome analysis Development (Cambridge, England) High 34180969
2016 ESE-3/EHF involved in co-regulation of ABCB1 (P-glycoprotein/MDR1) gene transcription via PXR (pregnane X receptor): ESE-3 binds a distal enhancer region containing DR4 motifs of the ABCB1 gene (confirmed by ChIP), and co-expression of ESE-3 with PXR in HepG2 cells enables rifampicin-induced reporter activation that is abolished by DR4 mutation. Knockdown of ESE-3 in LS180 cells reduces rifampicin-induced ABCB1 mRNA induction. ChIP (ESE-3 binding to ABCB1 enhancer), luciferase reporter assay with DR4 mutagenesis, siRNA knockdown, co-transfection in HepG2 cells Drug metabolism and pharmacokinetics Medium 27567379
2024 EHF deficiency in pancreatic cancer induces CXCL1 transcription (EHF represses CXCL1 promoter), leading to enhanced CXCR2+ neutrophil recruitment in a CXCL1-CXCR2-dependent manner that drives chemotherapy and immunotherapy resistance. TP53 mutation mediates loss of tumoral EHF. Nifurtimox elevates tumoral EHF and inhibits JAK1/STAT1 pathway to suppress CXCR2+ neutrophil recruitment. ChIP assay (EHF binding CXCL1 promoter), Ehf-knockout mice, KPC mouse model, humanized mice, single-cell RNA-seq, spatial transcriptomics, cytokine multiplex assay, CXCR2 blockade, neutrophil depletion Gastroenterology High 38492894
2024 EHF forms liquid-like nuclear condensates that transcriptionally repress TERT (reducing telomere length and driving senescence) and inflammatory factors (IL-6, CXCL12), thereby inducing cellular senescence without the associated inflammatory secretory phenotype (SASP) in PDAC cells. CRISPR/Cas9 library screening (SPiDER senescence probe-based), phase separation/condensate imaging, ChIP (EHF binding to TERT and inflammatory gene promoters), telomere length assay, flow cytometry, in vivo PDAC model Cancer letters Medium 39710057
2024 EHF interacts with the coactivator AJUBA LIM protein to cooperatively orchestrate transcriptional network activity in gastroesophageal adenocarcinoma, activating the KRAS signaling pathway. EHF expression is promoted by a core transcriptional regulatory circuitry composed of ELF3-KLF5-GATA6. Co-immunoprecipitation (EHF-AJUBA interaction), ChIP, reporter assay, siRNA knockdown, lipid nanoparticle dual targeting, in vitro and in vivo functional assays Acta pharmaceutica sinica. B Medium 38799645
2024 EHF transcriptionally activates GLI1 (glioma-associated oncogene homolog 1) and CCL2 (C-C motif chemokine 2) in cholangiocarcinoma by directly binding their promoters, thereby promoting tumor cell growth and recruiting/activating tumor-associated macrophages via the CCL2/CCR2 axis. ChIP (EHF binding to GLI1 and CCL2 promoters), reporter assay, in vitro and in vivo functional experiments, inhibitor combination (GANT58 + INCB3344) MedComm Medium 38741887
2024 In papillary thyroid cancer cells harboring concurrent BRAFV600E and TERT promoter mutations, EHF overexpression significantly increases TERT expression, and ChIP analysis suggested direct EHF binding to the mutant TERT promoter (but not wild-type TERT promoter). BRAF inhibition decreases both EHF and TERT expression. EHF overexpression and knockdown, ChIP-qPCR (TERT promoter), BRAF pharmacological inhibition, in vitro experiments The Journal of clinical endocrinology and metabolism Medium 39183149
2024 In salivary glands, Ehf (but not Elf5) plays a nonredundant role in ductal cell differentiation. EhfMut mice (CRISPR-Cas9 disruption of ETS domain) exhibit decreased granular convoluted tubules and accumulation of intercalated Sox9+ ductal cell populations, with a pronounced and sexually dimorphic phenotype. CRISPR-Cas9 mouse knockout (ETS domain disruption), immunostaining, histological analysis, cell population quantification Journal of dental research Medium 36348499
2024 Ehf deletion in the mammary gland impairs lobuloalveolar differentiation at late pregnancy (reduced milk genes, milk lipids, fewer differentiated alveolar cells, accumulation of alveolar progenitor cells). Ehf deletion attenuates prolactin-induced alveolar differentiation in mammary organoids and increases tumor incidence in the MMTV-PyMT mammary tumor model. Mouse Ehf knockout model, mammary organoids, histology, gene expression, MMTV-PyMT tumor model Developmental cell High 38781975
2024 RRAD (a GTPase) binds EHF and regulates its subcellular localization; RRAD negatively regulates glycolysis by controlling EHF's nucleocytoplasmic distribution. EHF (when nuclear) activates transcription of NEAT1_2, hexokinase 2, and pyruvate kinase M2, forming a NEAT1_2/RRAD/EHF positive feedback loop promoting glycolysis in papillary thyroid cancer cells. Co-immunoprecipitation (RRAD-EHF interaction), ChIP (EHF binding to NEAT1_2/HK2/PKM2 promoters), luciferase reporter assay, subcellular fractionation, in vitro and in vivo glycolysis assays Endocrinology Medium 37279586
2024 Dclk2 phosphorylates EHF and changes its nucleoplasmic distribution, causing p-EHF to exit the nucleus. Nuclear EHF represses Caspase1 and Caspase3 promoter activity; loss of nuclear EHF (due to Dclk2-mediated phosphorylation) promotes expression of Caspase1 and Caspase3 and stimulates neuronal pyroptosis. Kinase phosphorylation assay, subcellular fractionation/immunofluorescence, promoter reporter assay (Caspase1/3), siRNA knockdown, OGD and CCI mouse models Journal of cerebral blood flow and metabolism Medium 38513137
2024 EHF promotes M2 macrophage polarization in liver cancer by binding the promoter of KDM2B and transcriptionally activating it, leading to increased IL-6 secretion from TAMs which promotes liver cancer cell metastasis. CUT-Tag (EHF binding to KDM2B promoter), ChIP, luciferase assay, cytokine array, siRNA knockdown, co-culture system, in vitro and in vivo assays Cellular signalling Medium 39971220
2025 Loss of EHF in iPSC-derived lung cells enhances CFTR activity, increases transepithelial electrical resistance, leads to transcriptomic changes in basal cells, and reduces HIF-1α-mediated hypoxic response, revealing multiple mechanisms by which EHF modifies cystic fibrosis-related lung disease. CRISPR knockout of EHF in human iPSC-derived lung cells, electrophysiology (CFTR activity), transepithelial electrical resistance measurement, RNA-seq, HIF-1α response assay Disease models & mechanisms Medium 40590703
2026 EHF directly regulates Ccr7, Cd200, Cd274 (PD-L1), Irf4, and Rel expression in conventional dendritic cells (cDCs), as shown by CUT&TAG. Conditional deletion of EHF in DCs decreases CCR7, CD200, and PD-L1 expression, increases IRF4, decreases inhibitory NFκB member Rel, and promotes Th1- and Th17-biased CD4+ T cell responses. EHF expression is highly enriched in CCR7hi DCs in mice and humans. CUT&TAG (genome-wide EHF binding), conditional DC-specific knockout mice, flow cytometry, in vitro and in vivo T cell polarization assays, single-cell RNA-seq Nature communications High 41730908
2025 In prostate epithelial cells, EHF acts as a central transcriptional node controlling a hierarchy of regulatory factors and downstream signaling pathways (including COL1A1/DDR1, JAK/STAT3) to maintain epithelial lineage integrity. EHF knockout is sufficient to disrupt epithelial cell lineage integrity and promote a progenitor/stem-like state with basal and luminal features, attenuate androgenic response, and drive resistance to AR antagonists. EHF knockout mouse models, human epithelial cell knockout, transcriptome analysis, ChIP/binding assays, AR antagonist resistance assays bioRxivpreprint Medium bio_10.1101_2025.11.26.690649

Source papers

Stage 0 corpus · 79 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 ESE3/EHF controls epithelial cell differentiation and its loss leads to prostate tumors with mesenchymal and stem-like features. Cancer research 108 22505649
2018 ELF3, ELF5, EHF and SPDEF Transcription Factors in Tissue Homeostasis and Cancer. Molecules (Basel, Switzerland) 99 30200227
2000 ESE-3, a novel member of an epithelium-specific ets transcription factor subfamily, demonstrates different target gene specificity from ESE-1. The Journal of biological chemistry 97 10644770
2019 A novel miR-365-3p/EHF/keratin 16 axis promotes oral squamous cell carcinoma metastasis, cancer stemness and drug resistance via enhancing β5-integrin/c-met signaling pathway. Journal of experimental & clinical cancer research : CR 90 30782177
2001 The epithelium-specific ETS protein EHF/ESE-3 is a context-dependent transcriptional repressor downstream of MAPK signaling cascades. The Journal of biological chemistry 72 11259407
2016 Activation of the Lin28/let-7 Axis by Loss of ESE3/EHF Promotes a Tumorigenic and Stem-like Phenotype in Prostate Cancer. Cancer research 61 27197175
2008 Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation. Cell research 59 18475289
2007 Reduced expression and tumor suppressor function of the ETS transcription factor ESE-3 in prostate cancer. Oncogene 57 18037958
2017 Ets homologous factor (EHF) has critical roles in epithelial dysfunction in airway disease. The Journal of biological chemistry 54 28461336
2013 The Ets transcription factor EHF as a regulator of cornea epithelial cell identity. The Journal of biological chemistry 53 24142692
2016 ESE3 Inhibits Pancreatic Cancer Metastasis by Upregulating E-Cadherin. Cancer research 51 27923832
2024 Targeting ESE3/EHF With Nifurtimox Inhibits CXCR2+ Neutrophil Infiltration and Overcomes Pancreatic Cancer Resistance to Chemotherapy and Immunotherapy. Gastroenterology 42 38492894
2021 ESE3/EHF, a promising target of rosiglitazone, suppresses pancreatic cancer stemness by downregulating CXCR4. Gut 42 33674341
2021 Pancreatic cancer cell-derived microRNA-155-5p-containing extracellular vesicles promote immune evasion by triggering EHF-dependent activation of Akt/NF-κB signaling pathway. International immunopharmacology 40 34482266
2016 The ETS factor ESE3/EHF represses IL-6 preventing STAT3 activation and expansion of the prostate cancer stem-like compartment. Oncotarget 39 27732936
2002 Constitutive and cytokine-induced expression of the ETS transcription factor ESE-3 in the lung. American journal of respiratory cell and molecular biology 39 12444029
2015 Knockdown of EHF inhibited the proliferation, invasion and tumorigenesis of ovarian cancer cells. Molecular carcinogenesis 37 26258986
2011 A member of the ETS family, EHF, and the ATPase RUVBL1 inhibit p53-mediated apoptosis. EMBO reports 36 21617703
2021 EHF suppresses cancer progression by inhibiting ETS1-mediated ZEB expression. Oncogenesis 29 33712555
2001 Cow's milk-specific cellular and humoral immune responses and atopy skin symptoms in infants from atopic families fed a partially (pHF) or extensively (eHF) hydrolyzed infant formula. Allergy 29 11736743
2021 Activation of EHF via STAT3 phosphorylation by LMP2A in Epstein-Barr virus-positive gastric cancer. Cancer science 28 34014591
2013 The CF-modifying gene EHF promotes p.Phe508del-CFTR residual function by altering protein glycosylation and trafficking in epithelial cells. European journal of human genetics : EJHG 25 24105369
1999 Human chromosomal localization, tissue/tumor expression, and regulatory function of the ets family gene EHF. Biochemical and biophysical research communications 25 10527851
2015 The Transcription Factor Ehf Is Involved in TGF-β-Induced Suppression of FcεRI and c-Kit Expression and FcεRI-Mediated Activation in Mast Cells. Journal of immunology (Baltimore, Md. : 1950) 24 26297757
2019 The Edwardsiella piscicida Type III Effector EseJ Suppresses Expression of Type 1 Fimbriae, Leading to Decreased Bacterial Adherence to Host Cells. Infection and immunity 23 30988056
2020 EHF promotes colorectal carcinoma progression by activating TGF-β1 transcription and canonical TGF-β signaling. Cancer science 21 32372436
1998 Molecular cloning and expression of Ehf, a new member of the ets transcription factor/oncoprotein gene family. Biochemical and biophysical research communications 21 9600089
2005 Epithelial-specific transcription factor ESE-3 is involved in the development of monocyte-derived DCs. Blood 20 16380452
2022 Epithelial de-differentiation triggered by co-ordinate epigenetic inactivation of the EHF and CDX1 transcription factors drives colorectal cancer progression. Cell death and differentiation 18 35606410
2015 Abnormal Localization and Tumor Suppressor Function of Epithelial Tissue-Specific Transcription Factor ESE3 in Esophageal Squamous Cell Carcinoma. PloS one 18 25950810
2021 EHF is essential for epidermal and colonic epithelial homeostasis, and suppresses Apc-initiated colonic tumorigenesis. Development (Cambridge, England) 17 34180969
2017 Regulatory dynamics of 11p13 suggest a role for EHF in modifying CF lung disease severity. Nucleic acids research 17 28549169
2021 Loss of EHF facilitates the development of treatment-induced neuroendocrine prostate cancer. Cell death & disease 16 33414441
2016 Increased expression of EHF contributes to thyroid tumorigenesis through transcriptionally regulating HER2 and HER3. Oncotarget 16 27517321
2007 ESE-3, an Ets family transcription factor, is up-regulated in cellular senescence. Cancer science 16 17627613
2024 Ehf and Fezf2 regulate late medullary thymic epithelial cell and thymic tuft cell development. Frontiers in immunology 15 38420512
2013 The SRC family tyrosine kinase HCK and the ETS family transcription factors SPIB and EHF regulate transcytosis across a human follicle-associated epithelium model. The Journal of biological chemistry 13 23439650
2020 Edwardsiella piscicida type III protein EseJ suppresses apoptosis through down regulating type 1 fimbriae, which stimulate the cleavage of caspase-8. Cellular microbiology 12 32068939
2019 Coordinate regulation of ELF5 and EHF at the chr11p13 CF modifier region. Journal of cellular and molecular medicine 12 31557407
2021 EHF enhances malignancy by modulating AKT and MAPK/ERK signaling in non‑small cell lung cancer cells. Oncology reports 11 33907840
2023 NEAT1_2/RRAD/EHF Positive Feedback Loop Facilitates Aerobic Glycolysis in Papillary Thyroid Cancer Cells. Endocrinology 10 37279586
2022 Genetic Study of Elf5 and Ehf in the Mouse Salivary Gland. Journal of dental research 10 36348499
2022 The ETS Homologous Factor (EHF) Represents a Useful Immunohistochemical Marker for Predicting Prostate Cancer Metastasis. Diagnostics (Basel, Switzerland) 9 35453848
2012 Expression of ESE-3 isoforms in immunogenic and tolerogenic human monocyte-derived dendritic cells. PloS one 8 23185370
2005 Natural killer cell cytotoxic activity and c-Fos protein synthesis in rat hypothalamic cells after painful electric stimulation of the hind limbs and EHF irradiation of the skin. Medical science monitor : international medical journal of experimental and clinical research 8 16127352
2021 Ese-3 contributes to colon cancer progression by downregulating EHD2 and transactivating INPP4B. American journal of cancer research 7 33520362
2019 Proteasome inhibitor MG132 suppresses pancreatic ductal adenocarcinoma-cell migration by increasing ESE3 expression. Oncology letters 7 31897200
2014 Epithelium specific ETS transcription factor, ESE-3, of Protobothrops flavoviridis snake venom gland transactivates the promoters of venom phospholipase A2 isozyme genes. Toxicon : official journal of the International Society on Toxinology 7 25449102
2006 ESE-3 transcription factor is involved in the expression of death receptor (DR)-5 through putative Ets sites. Biochemical and biophysical research communications 7 17027647
2025 BRAF-induced EHF Expression Affects TERT in Aggressive Papillary Thyroid Cancer. The Journal of clinical endocrinology and metabolism 6 39183149
2016 Involvement of ESE-3, epithelial-specific ETS factor family member 3, in transactivation of the ABCB1 gene via pregnane X receptor in intestine-derived LS180 cells but not in liver-derived HepG2 cells. Drug metabolism and pharmacokinetics 6 27567379
2024 Transcription factor EHF drives cholangiocarcinoma development through transcriptional activation of glioma-associated oncogene homolog 1 and chemokine CCL2. MedComm 5 38741887
2024 Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma. Acta pharmaceutica Sinica. B 5 38799645
2024 The nuclear condensates of ESE3/EHF induce cellular senescence without the associated inflammatory secretory phenotype in pancreatic ductal adenocarcinoma. Cancer letters 5 39710057
2014 Activation of peroxisome proliferator-activated receptor gamma leads to upregulation of ESE-3 expression in human monocyte-derived dendritic cells. Scandinavian journal of immunology 5 24219556
1994 [The mechanism of synchronizing yeast cell cultures with EHF-radiation]. Biofizika 5 8043637
2024 Cpeb4-mediated Dclk2 promotes neuronal pyroptosis induced by chronic cerebral ischemia through phosphorylation of Ehf. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 4 38513137
2024 Ehf controls mammary alveolar lineage differentiation and is a putative suppressor of breast tumorigenesis. Developmental cell 4 38781975
2017 miR‑206 inhibits cancer initiating cells by targeting EHF in gastric cancer. Oncology reports 4 28714026
2014 Polymorphisms of EHF-ELF5 genomic region and its association with pediatric asthma in the Taiwanese population. Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi 4 25648666
2007 Responses of hypothalamic orexin-containing neurons to cyclophosphamide, EHF-irradiation of the skin, and their combination in rats. Pathophysiology : the official journal of the International Society for Pathophysiology 4 17881193
2025 EHF promotes liver cancer progression by meditating IL-6 secretion through transcription regulation of KDM2B in TAMs. Cellular signalling 3 39971220
2021 Ese-3 Inhibits the Proliferation, Migration, and Invasion of HaCaT Cells by Downregulating PSIP1 and NUCKS1. Annals of clinical and laboratory science 3 34452885
2025 LncRNA LINC01026 Is Overexpressed in Psoriasis and Enhances Keratinocyte Cell Cycle Progression by Regulating the Ets Homologous Factor (EHF). Journal of cellular and molecular medicine 2 40670887
2025 T3SS effector EseJ in Edwardsiella piscicida inhibits PANoptosis in macrophages. Communications biology 2 41044169
2008 Morphometric analysis of hypothalamic cells showing c-Fos proteins after movement restriction and EHF-irradiation. Pathophysiology : the official journal of the International Society for Pathophysiology 2 18313906
1995 [Significance of the functional state of blood phagocytes in the choice of optimal regime of EHF therapy of patients with pulmonary tuberculosis]. Problemy tuberkuleza 2 8524760
2025 Evaluating Type III Secretion System Genes (escE, esaE and eseJ) of Edwardsiella piscicida for Virulence in Japanese Flounder (Paralichthys olivaceus). Journal of fish diseases 1 40485376
2024 TMB Signature-Related RCAN2 Promotes Apoptosis by Upregulating EHF/DR5 Pathway in Hepatocellular Carcinoma. Frontiers in bioscience (Landmark edition) 1 39082336
2026 The transcription factor EHF promotes the maturation and immunosuppression of conventional dendritic cells. Nature communications 0 41730908
2026 Lung cancer cell-derived exosomal EHF drives M2 macrophage polarization via transcriptional activation of RNF41 to promote tumor progression. Regenerative therapy 0 41939996
2026 Sex-specific management of migraine a systematic review and consensus statement from the European Headache Federation (EHF). The journal of headache and pain 0 41998499
2026 Multiomics Reveals IL-17 Drives Epithelial Keratinization and Proliferation via EHF in Odontogenic Keratocysts. International journal of molecular sciences 0 42123694
2025 An in vitro model of the epithelial airway reveals a key function for EHF in lung homeostasis and disease. Disease models & mechanisms 0 40590703
2024 Codon Bias of the DDR1 Gene and Transcription Factor EHF in Multiple Species. International journal of molecular sciences 0 39409024
2023 [Retracted] miR‑206 inhibits cancer initiating cells by targeting EHF in gastric cancer. Oncology reports 0 37772393
2007 [Expression of c-Fos gene in the rat hypothalamus upon electric painful stimulation and EHF irradiation of the skin]. Rossiiskii fiziologicheskii zhurnal imeni I.M. Sechenova 0 17598468
2005 [Study of the systemic-organ blood circulation in acute period of the multiple trauma based on water-electrolytic metabolism and its correction with EHF-therapy]. Likars'ka sprava 0 16025675
1995 [The ultrastructural characteristics of the duodenal mucosa in peptic ulcer patients undergoing treatment with EHF-range electromagnetic radiation]. Likars'ka sprava 0 8630825

Missed literature

Know a paper Affinage missed for EHF? Flag it for the maintainers and the community.

No submissions yet.