Affinage

ZEB1

Zinc finger E-box-binding homeobox 1 · UniProt P37275

Length
1124 aa
Mass
124.1 kDa
Annotated
2026-06-11
100 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZEB1 is a dual zinc-finger/homeodomain transcription factor that binds E-box-like sequences (consensus CACCTG/AAAGGTGCA) through two distinct N- and C-terminal zinc-finger clusters and acts as both a context-dependent repressor and activator of target promoters (PMID:7935395, PMID:7588776). Its repressive output is executed by recruitment of corepressors: the general cofactor NC2 to a defined hydrophobic repression domain (PMID:9418848) and CtBP through PLDLS motifs whose mutation abolishes repression (PMID:10359772), with separable N- and C-terminal repressor domains targeting distinct lineage factors (PMID:10567522). Through this machinery ZEB1 directly represses a broad epithelial/differentiation program—p73, SEMA3F, ESRP1, MITF, miR-375, the T-cell chemokine CXCL10, and LIF—to drive EMT, invasion, dedifferentiation, and immune evasion (PMID:11713281, PMID:19177200, PMID:27500490, PMID:19515996, PMID:27270433, PMID:35288462). ZEB1 also functions as a direct or cofactor-assisted activator, partnering with p300 to potentiate Smad signaling (PMID:12743039), with Lef1 to activate invasion genes such as Prex1 (PMID:29903919), and with YAP/EP300 to drive H3K27Ac-dependent LPCAT3 transcription (PMID:37166352), and it directly activates metabolic genes including PFKM and PHGDH to reprogram glycolysis and serine synthesis (PMID:33897890, PMID:37331567). ZEB1 stability and activity are heavily post-translationally controlled: ATM phosphorylates and stabilizes ZEB1 to enable USP7-dependent CHK1 deubiquitylation and homologous-recombination DNA repair (PMID:25086746), multiple deubiquitinases (USP51, USP22, USP43, CSN5) and the antagonistic USP10/MEK-ERK axis set ZEB1 levels (PMID:29119051, PMID:36906615, PMID:36940483), and O-GlcNAcylation at Ser555 promotes its nuclear translocation and lipogenic-gene activation (PMID:35844792). In vivo conditional-knockout studies establish ZEB1 as a regulator of hematopoietic and leukemic stem cells, endothelial Notch/TGF-β signaling, osteoclast metabolism, and T-cell pathogenic differentiation, placing it at the intersection of EMT, the DNA-damage response, metabolic reprogramming, immunity, and stem-cell maintenance (PMID:33108352, PMID:31974363, PMID:36843552, PMID:34433042).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1994 Medium

    Established ZEB1 as a sequence-specific DNA-binding transcriptional repressor and defined its bipartite zinc-finger recognition architecture, answering what kind of regulator it is.

    Evidence DNA binding/Kd measurement, reporter assays, and immunocytochemistry defining the AAAGGTGCA site and nuclear/cytoplasmic shifts

    PMID:7935395

    Open questions at the time
    • Functional significance of the nuclear/cytoplasmic shift not mechanistically defined
    • Endogenous target genes not identified
  2. 1995 High

    Resolved that ZEB1's two zinc-finger clusters have distinct optimal binding sequences and that promoter context (presence of a GTTTC/G element) switches it between repressor and activator, explaining its dual transcriptional behavior.

    Evidence CASTing site selection, zinc-finger mutagenesis, and transient reporter assays

    PMID:7588776

    Open questions at the time
    • Cofactors mediating the activator vs repressor switch not yet identified
    • Homeodomain function beyond zinc-finger interaction unclear
  3. 1997 High

    Showed ZEB1 represses muscle differentiation by occupying E-boxes and is displaced by accumulating myogenic bHLH factors, providing a developmental logic for its repressive role.

    Evidence DNA binding, reporter assays, and overexpression differentiation assays targeting MEF-2

    PMID:9233803

    Open questions at the time
    • Corepressor identity not yet defined
    • Direct vs competitive displacement mechanism not fully resolved
  4. 1999 High

    Identified the corepressor machinery—NC2 and CtBP via PLDLS motifs—and separable lineage-specific repressor domains, defining how ZEB1 silences transcription mechanistically.

    Evidence In vitro transcription reconstitution, yeast two-hybrid, PLDLS-motif mutagenesis, and domain-swap reporter assays

    PMID:10359772 PMID:10567522 PMID:9418848

    Open questions at the time
    • Whether NC2 and CtBP act on the same or distinct target sets unresolved
    • Chromatin-level consequences not characterized in this era
  5. 2003 High

    Distinguished ZEB1 from ZEB2 functionally, showing ZEB1 recruits p300 to promote Smad-dependent activation whereas ZEB2 recruits CtBP to repress, establishing cofactor choice as the determinant of opposing signaling outputs.

    Evidence Reciprocal Co-IP, reporter assays, and in vivo Xenopus developmental epistasis

    PMID:12743039

    Open questions at the time
    • Signal determining p300 vs CtBP recruitment unknown
    • Structural basis of p300 interaction not defined
  6. 2009 High

    Demonstrated through in vivo ChIP that ZEB1 directly represses tissue-specific targets (p73, SEMA3F, MITF) to control proliferation, dedifferentiation, and tumor invasion, generalizing its repressive program.

    Evidence ChIP, shRNA/dominant-negative knockdown, and heterozygous mouse mutants

    PMID:11713281 PMID:19177200 PMID:19515996

    Open questions at the time
    • Genome-wide target catalog still incomplete
    • Cofactor requirements at these loci not mapped
  7. 2014 High

    Connected ZEB1 to the DNA-damage response, showing ATM phosphorylates and stabilizes ZEB1, which then promotes USP7-mediated CHK1 deubiquitylation and radioresistance—a non-transcriptional protein-stabilizing role.

    Evidence ATM kinase assay, Co-IP, CHK1 ubiquitination assay, and in vivo radioresistance models

    PMID:25086746

    Open questions at the time
    • ATM phosphosite(s) on ZEB1 not mapped here
    • Relationship between this function and ZEB1's transcriptional output unclear
  8. 2018 High

    Used genome-wide ChIP-seq and DNA-binding mutants to separate ZEB1's direct repression from Lef1-dependent indirect activation, mechanistically resolving its dual activator/repressor function at the chromatin level.

    Evidence ChIP-seq, RNA-seq, ZEB1 DNA-binding mutants, Lef1 Co-IP, and in vivo invasion assays

    PMID:29903919

    Open questions at the time
    • How ZEB1 is recruited by Lef1 without direct DNA binding not fully defined
    • Generalizability across tissues untested
  9. 2021 High

    Established ZEB1 as a direct transcriptional activator of metabolic genes (PFKM, PHGDH) via non-canonical promoter sites, revealing its role in glycolytic and serine-synthesis reprogramming with in vivo rescue validation.

    Evidence ChIP, luciferase assays, metabolic flux/isotope tracing, conditional KO mice, and PFKM/PHGDH rescue experiments

    PMID:33897890 PMID:37331567

    Open questions at the time
    • Cofactors enabling activation at non-canonical sites not identified
    • Whether these activation events require the acidic activation domain untested
  10. 2022 High

    Defined O-GlcNAcylation at Ser555 as a modification controlling ZEB1 nuclear translocation and lipogenic-gene activation, adding a metabolic-sensing PTM layer to ZEB1 regulation.

    Evidence Site-specific Ser555 mutagenesis, O-GlcNAcylation assay, subcellular fractionation, and ChIP for FASN/FADS2

    PMID:35844792

    Open questions at the time
    • Enzyme(s) adding/removing the O-GlcNAc mark not identified
    • Interplay with phosphorylation not resolved
  11. 2023 High

    Mapped the deubiquitinase/E3 network (USP22, USP43, USP10/MEK-ERK) and YAP/EP300 cofactor complexes controlling ZEB1 stability and chromatin activity, showing protein turnover is a major control node for ZEB1 output.

    Evidence Co-IP, ubiquitination assays, domain-mapping Co-IP, H3K27Ac/H2Bub ChIP, phosphosite mutagenesis, and in vivo metastasis models

    PMID:33391437 PMID:36906615 PMID:36940483 PMID:37166352

    Open questions at the time
    • Cognate E3 ligase(s) for ZEB1 not fully identified
    • Hierarchy among competing DUBs in a given cell type unclear
  12. 2023 High

    Conditional in vivo deletions across hematopoietic/leukemic stem cells, endothelium, osteoclasts, and T cells established ZEB1's physiological and tumor-suppressive/context-dependent roles beyond cancer-cell EMT.

    Evidence Tissue-specific conditional KO mice with transcriptomics, ChIP, metabolic flux, lineage tracing, and disease-model rescues (AML, osteoporosis, EAE, PAH)

    PMID:31974363 PMID:33108352 PMID:34433042 PMID:36166408 PMID:36843552

    Open questions at the time
    • Direct vs indirect targets in each tissue not exhaustively mapped
    • Reconciling tumor-suppressive (LSC) and oncogenic (EMT) roles mechanistically unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZEB1 integrates competing post-translational modifications, cofactor choice, and DNA-binding context into a single cell-type-specific transcriptional decision remains unresolved.
  • No unified model linking PTM state to activator vs repressor switching
  • Cognate E3 ligases and the full cofactor selection logic not defined
  • Structural basis of zinc-finger/homeodomain cooperation not solved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4 GO:0060089 molecular transducer activity 3 GO:0140097 catalytic activity, acting on DNA 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 3 R-HSA-73894 DNA Repair 1
Partners
CTBPEP300ID2LEF1P300USP22USP7YAP1

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 ZEB (vertebrate homolog of Drosophila Zfh-1) binds to a subset of E-box sequences in muscle gene promoters and actively represses transcription, inhibiting muscle differentiation by repressing MEF-2 family members; as myogenic bHLH proteins accumulate during differentiation, they displace ZEB from E-boxes, releasing repression. DNA binding assays, transcriptional reporter assays, overexpression in mammalian cells The EMBO journal High 9233803
1994 BZP (ZEB1) binds the 9-bp sequence AAAGGTGCA through two zinc finger clusters and functions as a transcriptional repressor of linked promoters; its subcellular localization shifts between nuclear (proliferating cells) and cytoplasmic (serum-deprived cells), correlating with its transcriptional inhibitory activity. DNA binding assays (Kd measurement), transcriptional reporter assays, immunocytochemistry, serum-deprivation experiments Molecular and cellular biology Medium 7935395
1995 AREB6 (ZEB1) has two zinc finger clusters with distinct optimal DNA binding sequences (N-terminal: GTCACCTGT/TGCACCTGT; C-terminal: C/TACCTG/TT); the homeodomain lacks specific DNA binding but interacts with the N-terminal zinc finger cluster. Depending on the presence of an additional GTTTC/G consensus sequence, AREB6 can either repress or activate transcription from the same CACCTGT-containing promoter. CASTing (cyclic amplification and selection of targets), zinc-finger mutagenesis, transient transfection reporter assays European journal of biochemistry High 7588776
1998 AREB6 (ZEB1) contains a hydrophobic repression domain (aa 754–901) and an acidic activation domain (aa 1011–1124). The repression domain requires the general transcriptional cofactor NC2 (NC2α/DRAP1 and NC2β/Dr1): it represses transcription in HeLa nuclear extract but not in a reconstituted system lacking NC2; addition of recombinant NC2 restores repressor activity. Direct interaction between the AREB6 repression domain and NC2α was demonstrated by yeast two-hybrid. In vitro transcription reconstitution assay, recombinant protein addition, yeast two-hybrid, transient transfection domain-mapping Molecular and cellular biology High 9418848
1999 ZEB and its Drosophila ortholog zfh-1 interact with corepressor CtBP through PLDLS motifs; ZEB contains three CtBP-binding sites whose mutation abolishes both CtBP binding and repressor activity, demonstrating that CtBP recruitment to the promoter is necessary for ZEB-mediated transcriptional repression. Co-immunoprecipitation, mutagenesis of PLDLS motifs, transcriptional reporter assays, promoter recruitment assays Proceedings of the National Academy of Sciences of the United States of America High 10359772
1999 ZEB contains two independent repressor domains with distinct tissue specificities: the C-terminal domain inhibits muscle differentiation by specifically blocking MEF2C transcriptional activity, while the N-terminal domain represses hematopoietic transcription factors (c-myb, ets family members, TFE-III) in T lymphocytes. Domain-swap constructs, transcriptional reporter assays, co-expression with specific transcription factors in mammalian cells Molecular and cellular biology High 10567522
2001 ZEB binds six consensus E-box sites in the first intron of p73 both in vitro and in vivo (chromatin immunoprecipitation), repressing p73 transcription during cell proliferation; expression of dominant-negative ZEB (ZEB-DB) derepresses p73 in proliferating C2C12 and P19 cells. ChIP, EMSA, dominant-negative ZEB expression, RT-PCR Molecular and cellular biology High 11713281
2002 Zfhep/ZEB1 is post-translationally modified by phosphorylation on Ser/Thr residues; PP2A dephosphorylates the slower-mobility (hyperphosphorylated) form. Phosphorylation is cell-type-specific, with different cell lines expressing predominantly phosphorylated or non-phosphorylated forms. Western blot (mobility shift), phosphatase treatment (PP2A), O-GlcNAcase treatment (negative) Biochemical and biophysical research communications Medium 12163027
2003 ZEB1/deltaEF1 synergizes with Smad-mediated transcriptional activation by binding to p300 and promoting formation of a p300-Smad transcriptional complex, whereas ZEB2/SIP1 represses Smad signaling by recruiting CtBP. These opposing effects on TGFβ/BMP target genes were demonstrated in vitro and in vivo in Xenopus development. Co-immunoprecipitation, transcriptional reporter assays, in vivo Xenopus developmental assays, dominant-negative constructs The EMBO journal High 12743039
2003 ZEB directly binds the ZV element (CAGGTA sequence) within the BZLF1 promoter of Epstein-Barr virus, functioning as the cellular repressor ZVR; overexpression of ZEB in B-lymphocytic and mammary epithelial cells represses Zta-induced BZLF1 promoter activity four- to fivefold via this ZV site. Immunoshift assay with anti-deltaEF1 antibody, competition EMSA, reporter assay with ZV site mutations Journal of virology High 12477825
2006 NF-κB (p65) transcriptionally activates the ZEB1 promoter; overexpression of ZEB1 reduces E-cadherin and p63 expression and induces EMT in MCF10A cells; siRNA knockdown of ZEB1 reduces viability of NF-κB-activated but not parental cells. Promoter-luciferase reporter assay, ZEB1 overexpression, siRNA knockdown, E-cadherin protein measurement Oncogene Medium 16862183
2009 Zeb1 binds the Mitf-A promoter in vivo (by chromatin immunoprecipitation) and represses Mitf transcription; heterozygous mutation or shRNA knockdown of Zeb1 prevents RPE dedifferentiation (loss of pigment, proliferation, and epithelial morphology) through derepression of Mitf. ChIP, shRNA knockdown, heterozygous mouse mutant, RT-PCR Investigative ophthalmology & visual science High 19515996
2009 ZEB-1 directly binds to two conserved E-box sites in the SEMA3F gene (confirmed by ChIP) and represses its transcription in lung cancer cells; ZEB-1 levels specifically correlate with SEMA3F repression, and HDAC inhibitor treatment reduces ZEB-1 binding and restores SEMA3F expression. ChIP, ZEB-1 overexpression and siRNA knockdown, RT-PCR, HDAC inhibitor treatment Neoplasia (New York, N.Y.) High 19177200
2011 ZEB1 drives EMT in lung cancer by directly repressing ESRP1, leading to increased expression of a mesenchymal splice variant of CD44 and a more invasive phenotype. ZEB1 overexpression and knockdown, splice variant analysis, invasion assays The Journal of clinical investigation Medium 27500490
2014 ATM phosphorylates and stabilizes ZEB1 in response to DNA damage; ZEB1 in turn directly interacts with USP7 and enhances USP7-mediated deubiquitylation and stabilization of CHK1, promoting homologous recombination-dependent DNA repair and radioresistance. Co-immunoprecipitation, phosphorylation assays, ATM kinase assay, USP7-ZEB1 binding, CHK1 ubiquitination assay, in vitro and in vivo radioresistance Nature cell biology High 25086746
2015 Zeb1 promotes expression of a-series glycosphingolipids by binding to the St3gal5 (GM3 synthase) promoter and suppressing microRNA-mediated repression of St3gal5, thereby modulating epithelial cell adhesion. Promoter binding assay (ChIP), miRNA suppression analysis, St3gal5 knockdown/overexpression, cell adhesion assays EMBO reports Medium 25643708
2016 ZEB1 transcriptionally activates VEGFA by increasing SP1 recruitment to the VEGFA promoter via PI3K and p38 pathway activation, promoting tumor angiogenesis in breast cancer. ChIP (SP1 recruitment), ZEB1 overexpression/knockdown, pathway inhibitors (PI3K, p38), VEGFA reporter assay, HUVEC tube formation assay PloS one Medium 26882471
2016 In EGFR-mutated lung cancer cells, ZEB1 suppresses tumor cell growth by increasing miR-200 targets to antagonize ERBB3; NOTCH1, a miR-200 target, represses ERBB3 promoter activity, placing ZEB1 upstream of a NOTCH1-ERBB3 growth-suppressive axis. ZEB1 knockdown/overexpression, ERBB3 promoter reporter assay, miR-200 target analysis, genetic epistasis Nature communications Medium 27456471
2017 USP51 binds, deubiquitinates, and stabilizes ZEB1 protein; depletion of USP51 leads to ZEB1 protein downregulation, mesenchymal-to-epithelial shift, and inhibition of cell invasion in breast cancer cells. Deubiquitinase library screen, Co-immunoprecipitation, ubiquitination assay, USP51 knockdown/overexpression, invasion assays American journal of cancer research High 29119051
2017 ZEB1 directly represses transcription of T cell-attracting chemokines including CXCL10 in melanoma cells (confirmed by ChIP), thereby impairing CD8+ T cell recruitment and promoting immune evasion. ChIP, ZEB1 gain/loss-of-function in syngeneic mouse models, flow cytometry, multiplex cytokine analysis Journal for immunotherapy of cancer High 35288462
2017 CSN5 directly binds ZEB1 and decreases its ubiquitination, enhancing ZEB1 protein stability and promoting EMT and metastasis in renal cell carcinoma. Co-immunoprecipitation, ubiquitination assay, CSN5 knockdown, invasion/migration assays Biochemical and biophysical research communications Medium 28479251
2017 ZEB1 controls production of inflammatory cytokines IL-6 and IL-8 in breast cancer cells, as identified by ChIP-seq showing ZEB1 binding to genomic regions near these cytokine genes, with ZEB1 knockdown reducing their expression. ChIP-seq, RNA-seq, GSEA, antibody array, ELISA, ZEB1 knockdown Molecular oncology Medium 28618162
2017 ZEB1 in stromal fibroblasts increases acetylation and expression of p53, which is then recruited to FGF2/7, VEGF, and IL6 promoters; ZEB1 deletion in fibroblasts reduces their secretion into the tumor stroma, and p53 ablation rescues impaired tumor growth in ZEB1-deleted stroma—establishing a ZEB1/p53 axis in cancer-associated fibroblasts. Conditional ZEB1 knockout in fibroblasts (mouse model), p53 acetylation assay, ChIP, cytokine measurement, genetic rescue (p53 knockout) Nature communications High 31324807
2017 ZEB1 directly represses the miR-375 gene in prostate cancer; miR-375 in turn targets YAP1, establishing a ZEB1-miR-375-YAP1 regulatory circuit controlling epithelial plasticity and invasion. ZEB1 ChIP on miR-375 promoter, miR-375 overexpression and knockdown, YAP1 reporter assay, invasion assays Oncogene Medium 27270433
2018 In glioblastoma stem-like cells, Zeb1 binds chromatin at both active and repressed gene loci genome-wide; transcriptional repression requires direct DNA binding of Zeb1, while gene activation occurs through indirect recruitment to regulatory regions by Lef1 (Wnt pathway effector), independently of Wnt signaling. ZEB1/Lef1 complex activates the GEF Prex1, which promotes glioblastoma cell invasion in vivo. ChIP-seq, RNA-seq, ZEB1 DNA-binding mutants, Lef1 Co-IP and co-binding analysis, in vivo invasion assay The EMBO journal High 29903919
2018 Simultaneous deletion of Zeb1 restores directional migration to Ovol2-deficient hair follicle bulge stem cells, establishing Zeb1 as a downstream effector of the Ovol2-Zeb1 EMT circuit that controls directional migration in skin epithelial regeneration. Conditional double knockout (Ovol2 and Zeb1), live imaging of wound explants and hair follicle stem cells, cell cycle analysis EMBO reports High 30413481
2019 Thyroid hormone (T3) transcriptionally upregulates ZEB1 expression in squamous cell carcinoma cells, and elevated ZEB1 promotes EMT and metastatic transformation, establishing TH/D2 as an upstream regulator of the ZEB1-E-cadherin switch. ZEB1 reporter assay, ZEB1 overexpression/knockdown, in vivo tumor models, T3-treatment experiments Nature communications Medium 31776338
2019 FOXE1 directly interacts with the ZEB1 promoter and activates its transcription in thyroid cancer cells; ZEB1 silencing decreases migration and invasion, placing ZEB1 downstream of FOXE1 in thyroid cancer EMT. Promoter ChIP, ZEB1 knockdown/overexpression, FOXE1 gain/loss-of-function, migration and invasion assays Endocrine-related cancer Medium 31846430
2020 Endothelial ZEB1 deletion reduces histone acetylation on Dll4 and Notch1 promoters, epigenetically suppressing Notch signaling in bone vasculature, thereby impairing CD31hi/endomucinhi vessel formation and osteogenesis; delivery of Zeb1-packaged liposomes to osteoporotic mice restores Notch activity. Endothelial-specific ZEB1 conditional knockout mice, ChIP (histone acetylation), Notch signaling reporters, bone phenotype analysis, liposome delivery rescue Nature communications High 31974363
2020 Endothelial ZEB1 deletion elicits persistent tumor vascular normalization by epigenetically repressing TGF-β signaling, improving blood/oxygen perfusion and immune cell infiltration, and reducing tumor growth and metastasis. Endothelial-specific ZEB1 conditional knockout in tumor-bearing mice, ChIP (epigenetic repression of TGF-β pathway), tumor perfusion measurements, immune cell profiling The Journal of clinical investigation High 32039918
2020 ZEB1 promotes CD4+ T cell pathogenic Th1 and Th17 differentiation by inhibiting miR-101-3p, which would otherwise repress JAK2 expression; this disinhibits JAK2 and downstream STAT3/STAT4 phosphorylation, enabling IL-17 and IFN-γ expression. ZEB1 deletion protects against EAE (mouse MS model). Conditional ZEB1 knockout in T cells, miR-101-3p overexpression/inhibition, JAK2 and STAT3/4 phosphorylation assays, cytokine measurement, EAE model Cell reports High 34433042
2021 ZEB1 transcriptionally activates PFKM (phosphofructokinase-1 muscle isoform) by binding a non-canonical binding sequence in its promoter (confirmed by ChIP and luciferase assay), enhancing glycolysis and Warburg effect; ZEB1 knockdown impairs PFKM expression and glycolysis, rescued by exogenous PFKM. ChIP, luciferase reporter assay, ZEB1 shRNA knockdown, metabolic assays (glucose uptake, ECAR, OCR), rescue with PFKM re-expression, orthotopic xenograft Theranostics High 33897890
2021 ZEB1 directly represses LIF in glioma stem cells; ZEB1 knockdown induces LIF, promoting GCSC self-renewal; IFN-γ treatment induces ZEB1 expression and attenuates LIF-driven stemness. ZEB1 binding sites were identified within the LIF promoter. ZEB1 promoter binding site analysis, ZEB1 knockdown, LIF induction assay, self-renewal assay, IFN-γ treatment Scientific reports Medium 28246407
2021 Conditional acute deletion of Zeb1 in hematopoietic stem cells causes self-renewal defect, multilineage differentiation block, apoptosis-driven thymocyte loss, and upregulation of EpCAM; Zeb1 KO in leukemic stem cells accelerates AML progression, establishing Zeb1 as a tumor suppressor in LSCs. Mx1-Cre conditional knockout, transcriptomic analysis, bone marrow transplantation, AML model (MLL-AF9, Meis1a/Hoxa9) The Journal of clinical investigation High 33108352
2022 O-GlcNAcylation of ZEB1 at Ser555 enhances its stabilization and nuclear translocation; this promotes transcription of lipogenesis genes FASN and FADS2, resulting in lipid peroxidation-dependent ferroptosis in mesenchymal pancreatic cancer cells under high-glucose conditions. Site-specific mutagenesis (Ser555), O-GlcNAcylation assay, subcellular fractionation, ChIP/reporter for FASN/FADS2, ferroptosis cell death assay International journal of biological sciences High 35844792
2022 ZEB directly binds the LPCAT3 promoter (-1600 to -1401 nt region) to stimulate its transcription in a YAP-dependent manner; ZEB and YAP physically interact through ZEB's zinc-finger cluster domain and YAP's WW domain; EP300 simultaneously binds YAP (via Bromo domain) and ZEB (via CBP/p300-HAT domain) and induces H3K27Ac at the LPCAT3 locus. ChIP, reporter assay, domain-specific binding assays (Co-IP with domain mutants), H3K27Ac ChIP Antioxidants & redox signaling High 37166352
2023 USP10 binds ZEB1 and promotes its proteasomal degradation by modifying ZEB1 ubiquitination; MEK-ERK signaling phosphorylates USP10 at Ser236, impairing the USP10-ZEB1 interaction and enabling ZEB1 protein stabilization, which promotes colorectal cancer metastatic colonization. Co-immunoprecipitation, ubiquitination assay, MEK-ERK inhibitor treatment, USP10 phospho-site mutagenesis, tail vein metastasis mouse model Molecular cancer research : MCR High 36940483
2023 USP43 physically interacts with ZEB1 (Co-IP), deubiquitinates it, and stabilizes the ZEB1 protein, promoting proliferation, migration, and invasion of colorectal cancer cells. Co-immunoprecipitation, ubiquitination assay, USP43 overexpression/knockdown, invasion/migration assays Journal of Cancer Medium 33391437
2023 ZEB1 transcriptionally activates PHGDH by binding a non-classical binding site in its promoter (confirmed by ChIP and luciferase assay), driving serine synthesis pathway flux; conditional liver-specific Zeb1 knockout impairs PHGDH expression and HCC carcinogenesis, rescued by exogenous PHGDH expression. ChIP, luciferase reporter assay, [13C]-glucose metabolic tracing, liver-specific conditional Zeb1 KO mouse, PHGDH rescue experiments, orthotopic xenograft Cellular and molecular gastroenterology and hepatology High 37331567
2023 In osteoclasts, Zeb1 transcriptionally represses MtCK1 (mitochondrial creatine kinase 1), thereby controlling the phosphocreatine energy shuttle and mitochondrial respiration; Zeb1-null osteoclasts are hyperactivated and cause excessive bone resorption in vivo, identifying a Zeb1/MtCK1 metabolic axis controlling osteoclast activity. Conditional Zeb1 knockout in osteoclasts, ChIP (Zeb1 binding to MtCK1 locus), metabolic flux assays (phosphocreatine shuttle, mitochondrial respiration), in vivo bone density measurement The EMBO journal High 36843552
2023 USP22 acts as a co-activator of ZEB1-mediated VEGFA transcription by maintaining ZEB1 stability via deubiquitinase activity and being recruited to ZEB1-binding elements on the VEGFA promoter, where it alters histone H2Bub levels to enhance transcription. Co-immunoprecipitation, ubiquitination assay, ChIP (USP22 and ZEB1 at VEGFA promoter), H2Bub ChIP, USP22 knockdown/overexpression, tumor xenograft Cell death & disease High 36906615
2023 BMPR1A activation induces ID2 to physically interact with and sequester ZEB1, attenuating ZEB1-driven transcription of Tgfbr2 and preventing excessive endothelial-to-mesenchymal transition; endothelial-specific Bmpr1a deletion causes PAH in mice, rescued by siRNA against Tgfbr2. Co-immunoprecipitation (ID2-ZEB1 interaction), endothelial-specific Bmpr1a conditional KO mouse, lineage tracing, siRNA-lipid nanoparticle rescue, TGFBR2 expression analysis Cardiovascular research High 36166408
2016 Dephosphorylation of the Retinoblastoma protein (Rb) is associated with ZEB1 physical interaction (co-immunoprecipitation), and leads to inhibition of ZEB1 transcriptional activity, reducing EMT in mesenchymal cancer cells in 3D Matrigel culture. Co-immunoprecipitation (Rb-ZEB1), PNUTS shRNA-mediated Rb dephosphorylation, transcriptional activity assay, 3D Matrigel invasion assay Cancer biology & therapy Medium 27645778
2013 In glioblastoma, ZEB1 is a central regulator interconnecting invasion, chemoresistance, and tumorigenesis through the ZEB1-miR-200 feedback loop, with downstream effectors ROBO1, c-MYB, and MGMT identified as novel ZEB1 pathway targets. ZEB1 knockdown and overexpression, miR-200 manipulation, invasion and chemoresistance assays, target gene expression analysis EMBO molecular medicine Medium 23818228
2019 ZEB1 directly activates transcription of the CD47 gene in hypoxic cervical cancer cells (confirmed by transcriptional activation assay); exosomal ZEB1 retains transcriptional activity and reprograms macrophages toward SIRPα+ TAM polarization via STAT3 signaling, promoting immune evasion. Reporter/transcriptional assay for CD47, exosome isolation and transfer experiments, STAT3 signaling inhibition, in vivo xenograft phagocytosis assays Cell communication and signaling : CCS Medium 38183060

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nature reviews. Cancer 2654 17508028
2010 The ZEB/miR-200 feedback loop--a motor of cellular plasticity in development and cancer? EMBO reports 695 20706219
2006 NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 531 16862183
2015 ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell cycle (Georgetown, Tex.) 505 25607528
2009 The role of the ZEB family of transcription factors in development and disease. Cellular and molecular life sciences : CMLS 404 19011757
2014 ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nature cell biology 384 25086746
2013 The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance. EMBO molecular medicine 326 23818228
2003 Regulation of Smad signaling through a differential recruitment of coactivators and corepressors by ZEB proteins. The EMBO journal 303 12743039
2016 ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. The Journal of clinical investigation 279 27500490
2017 Pleiotropic Roles for ZEB1 in Cancer. Cancer research 262 29254997
1999 ZEB represses transcription through interaction with the corepressor CtBP. Proceedings of the National Academy of Sciences of the United States of America 246 10359772
2012 ZEB/miR-200 feedback loop: at the crossroads of signal transduction in cancer. International journal of cancer 217 22753312
2021 ZEB1 enhances Warburg effect to facilitate tumorigenesis and metastasis of HCC by transcriptionally activating PFKM. Theranostics 138 33897890
2012 Evolutionary functional analysis and molecular regulation of the ZEB transcription factors. Cellular and molecular life sciences : CMLS 137 22349261
2020 Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis. Nature communications 132 31974363
2020 ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance. Frontiers in molecular biosciences 131 32266287
1997 ZEB, a vertebrate homolog of Drosophila Zfh-1, is a negative regulator of muscle differentiation. The EMBO journal 125 9233803
2018 The roles of ZEB1 in tumorigenic progression and epigenetic modifications. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 117 30530042
2001 The transcriptional repressor ZEB regulates p73 expression at the crossroad between proliferation and differentiation. Molecular and cellular biology 108 11713281
2016 ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors. EMBO molecular medicine 105 27596438
2011 A NOTCH3-mediated squamous cell differentiation program limits expansion of EMT-competent cells that express the ZEB transcription factors. Cancer research 99 21890822
2023 LPCAT3 Is Transcriptionally Regulated by YAP/ZEB/EP300 and Collaborates with ACSL4 and YAP to Determine Ferroptosis Sensitivity. Antioxidants & redox signaling 97 37166352
2022 Senescent cell population with ZEB1 transcription factor as its main regulator promotes osteoarthritis in cartilage and meniscus. Annals of the rheumatic diseases 95 36564153
2017 ZEB1-regulated inflammatory phenotype in breast cancer cells. Molecular oncology 92 28618162
2016 A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer. Oncogene 91 27270433
2010 ZEB proteins link cell motility with cell cycle control and cell survival in cancer. Cell cycle (Georgetown, Tex.) 85 20160487
1995 DNA binding through distinct domains of zinc-finger-homeodomain protein AREB6 has different effects on gene transcription. European journal of biochemistry 85 7588776
1999 Independent repressor domains in ZEB regulate muscle and T-cell differentiation. Molecular and cellular biology 83 10567522
2011 Epithelial-mesenchymal transition and mesenchymal-epithelial transition via regulation of ZEB-1 and ZEB-2 expression in pancreatic cancer. Journal of surgical oncology 82 22213144
2013 Clinical implication of ZEB-1 and E-cadherin expression in hepatocellular carcinoma (HCC). BMC cancer 74 24304617
2022 ZEB1 transcription factor promotes immune escape in melanoma. Journal for immunotherapy of cancer 72 35288462
2020 MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy. Biomolecules 70 32664703
2017 USP51 promotes deubiquitination and stabilization of ZEB1. American journal of cancer research 70 29119051
2003 ZEB negatively regulates the lytic-switch BZLF1 gene promoter of Epstein-Barr virus. Journal of virology 68 12477825
2016 A genetic cell context-dependent role for ZEB1 in lung cancer. Nature communications 61 27456471
2014 Zeb1 and Snail1 engage miR-200f transcriptional and epigenetic regulation during EMT. International journal of cancer 59 25178837
2022 Regulation of ZEB1 Function and Molecular Associations in Tumor Progression and Metastasis. Cancers 58 35454770
2019 Thyroid hormone induces progression and invasiveness of squamous cell carcinomas by promoting a ZEB-1/E-cadherin switch. Nature communications 57 31776338
2020 Clonal ZEB1-Driven Mesenchymal Transition Promotes Targetable Oncologic Antiangiogenic Therapy Resistance. Cancer research 55 32041837
2020 Identification of a Zeb1 expressing basal stem cell subpopulation in the prostate. Nature communications 54 32024836
2015 Zeb1 affects epithelial cell adhesion by diverting glycosphingolipid metabolism. EMBO reports 52 25643708
2009 Zeb1 represses Mitf and regulates pigment synthesis, cell proliferation, and epithelial morphology. Investigative ophthalmology & visual science 52 19515996
2019 A ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumours. Nature communications 51 31324807
2016 ZEB1 Upregulates VEGF Expression and Stimulates Angiogenesis in Breast Cancer. PloS one 51 26882471
2022 O-GlcNAcylation of ZEB1 facilitated mesenchymal pancreatic cancer cell ferroptosis. International journal of biological sciences 50 35844792
2012 Expression of snail, twist, and Zeb1 in malignant mesothelioma. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 50 23030626
2009 ZEB-1, a repressor of the semaphorin 3F tumor suppressor gene in lung cancer cells. Neoplasia (New York, N.Y.) 49 19177200
2021 Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia. The Journal of clinical investigation 48 33108352
2008 Expression of the ZEB1 (deltaEF1) transcription factor in human: additional insights. Molecular and cellular biochemistry 48 18622689
2018 Zeb1 potentiates genome-wide gene transcription with Lef1 to promote glioblastoma cell invasion. The EMBO journal 47 29903919
2010 ZEB1 in Pancreatic Cancer. Cancers 47 24281177
1998 Involvement of negative cofactor NC2 in active repression by zinc finger-homeodomain transcription factor AREB6. Molecular and cellular biology 47 9418848
2017 ZEB1 Regulates Multiple Oncogenic Components Involved in Uveal Melanoma Progression. Scientific reports 44 28246385
2021 ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis. Cell reports 43 34433042
2017 CSN5 promotes renal cell carcinoma metastasis and EMT by inhibiting ZEB1 degradation. Biochemical and biophysical research communications 43 28479251
1994 BZP, a novel serum-responsive zinc finger protein that inhibits gene transcription. Molecular and cellular biology 43 7935395
2021 ZEB1: New advances in fibrosis and cancer. Molecular and cellular biochemistry 42 33417164
2003 Expression of Zfhep/deltaEF1 protein in palate, neural progenitors, and differentiated neurons. Gene expression patterns : GEP 42 14643678
2017 ZEB1 expression is a potential indicator of invasive endometriosis. Acta obstetricia et gynecologica Scandinavica 41 28597474
2020 Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies. The Journal of clinical investigation 38 32039918
2021 USP43 directly regulates ZEB1 protein, mediating proliferation and metastasis of colorectal cancer. Journal of Cancer 36 33391437
2017 Long Noncoding RNA-1604 Orchestrates Neural Differentiation through the miR-200c/ZEB Axis. Stem cells (Dayton, Ohio) 35 29205638
2020 Zeb1 for RCP-induced oral cancer cell invasion and its suppression by resveratrol. Experimental & molecular medicine 34 32728068
2019 ZEB1 promotes tumorigenesis and metastasis in hepatocellular carcinoma by regulating the expression of vimentin. Molecular medicine reports 34 30664206
2016 Dephosphorylation of the Retinoblastoma protein (Rb) inhibits cancer cell EMT via Zeb. Cancer biology & therapy 34 27645778
2022 ZEB1: Catalyst of immune escape during tumor metastasis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 33 36076506
2018 An Ovol2-Zeb1 transcriptional circuit regulates epithelial directional migration and proliferation. EMBO reports 33 30413481
2002 Cell-specific phosphorylation of Zfhep transcription factor. Biochemical and biophysical research communications 33 12163027
2019 Protein kinase C inhibitors override ZEB1-induced chemoresistance in HCC. Cell death & disease 32 31543517
2017 Clinicopathological significance of ZEB-1 and E-cadherin proteins in patients with oral cavity squamous cell carcinoma. OncoTargets and therapy 32 28243114
1996 Alternative splicing gives rise to two isoforms of Zfhep, a zinc finger/homeodomain protein that binds T3-response elements. DNA and cell biology 30 8769566
2023 USP10 Regulates ZEB1 Ubiquitination and Protein Stability to Inhibit ZEB1-Mediated Colorectal Cancer Metastasis. Molecular cancer research : MCR 29 36940483
2021 EHF suppresses cancer progression by inhibiting ETS1-mediated ZEB expression. Oncogenesis 29 33712555
2021 miR-34a inhibits melanoma growth by targeting ZEB1. Aging 29 34102608
2017 ZEB1 regulates glioma stemness through LIF repression. Scientific reports 29 28246407
2022 Ets family proteins regulate the EMT transcription factors Snail and ZEB in cancer cells. FEBS open bio 28 35451213
2001 Developmental and functional evidence of a role for Zfhep in neural cell development. Brain research. Molecular brain research 28 11731009
2022 Post-Translational Modification of ZEB Family Members in Cancer Progression. International journal of molecular sciences 27 36499447
2020 Intrinsic Balance between ZEB Family Members Is Important for Melanocyte Homeostasis and Melanoma Progression. Cancers 27 32796736
2017 Generation and characterization of mice for conditional inactivation of Zeb1. Genesis (New York, N.Y. : 2000) 26 28176446
2021 Expression and Function of ZEB1 in the Cornea. Cells 25 33923743
2019 Long noncoding RNA MAGI1-IT1 promoted invasion and metastasis of epithelial ovarian cancer via the miR-200a/ZEB axis. Cell cycle (Georgetown, Tex.) 25 31122127
2017 ZEB1 promotes prostate cancer proliferation and invasion through ERK1/2 signaling pathway. European review for medical and pharmacological sciences 25 29028100
2020 FOXE1 regulates migration and invasion in thyroid cancer cells and targets ZEB1. Endocrine-related cancer 24 31846430
2019 IGFBP2 upregulates ZEB1 expression and promotes hepatocellular carcinoma progression through NF-κB signaling pathway. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 24 31818638
2018 ZEB Proteins in Leukemia: Friends, Foes, or Friendly Foes? HemaSphere 24 31723771
2023 ZEB1 Transcriptionally Activates PHGDH to Facilitate Carcinogenesis and Progression of HCC. Cellular and molecular gastroenterology and hepatology 23 37331567
2020 TCF4 promotes colorectal cancer drug resistance and stemness via regulating ZEB1/ZEB2 expression. Protoplasma 23 31933004
2020 TGFβ mediated LINC00273 upregulation sponges mir200a-3p and promotes invasion and metastasis by activating ZEB1. Journal of cellular physiology 23 32017082
2017 Expression of and correlation between BCL6 and ZEB family members in patients with breast cancer. Experimental and therapeutic medicine 23 29104620
2023 BMPR1A promotes ID2-ZEB1 interaction to suppress excessive endothelial to mesenchymal transition. Cardiovascular research 22 36166408
2022 The role of the ZEB1-neuroinflammation axis in CNS disorders. Journal of neuroinflammation 22 36402997
2018 Naringin targets Zeb1 to suppress osteosarcoma cell proliferation and metastasis. Aging 22 30580326
2011 Androgen Receptor Regulates Transcription of the ZEB1 Transcription Factor. International journal of endocrinology 22 22190929
2020 Zeb1 promotes corneal neovascularization by regulation of vascular endothelial cell proliferation. Communications biology 21 32620870
2024 Hypoxia-induced ZEB1 promotes cervical cancer immune evasion by strengthening the CD47-SIRPα axis. Cell communication and signaling : CCS 20 38183060
2020 Musashi2 promotes the progression of pancreatic cancer through a novel ISYNA1-p21/ZEB-1 pathway. Journal of cellular and molecular medicine 20 32779876
2020 Palmitate-Induced IRE1-XBP1-ZEB Signaling Represses Desmoplakin Expression and Promotes Cancer Cell Migration. Molecular cancer research : MCR 20 33106375
2023 A Zeb1/MtCK1 metabolic axis controls osteoclast activation and skeletal remodeling. The EMBO journal 19 36843552
2023 USP22 upregulates ZEB1-mediated VEGFA transcription in hepatocellular carcinoma. Cell death & disease 19 36906615

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