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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 15 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
GRHL3
grainyhead like transcription factor 3
Chromosome 1 Β· 1p36.11
NCBI Gene: 57822Ensembl: ENSG00000158055.17HGNC: HGNC:25839UniProt: Q8TE85
54PubMed Papers
21Diseases
0Drugs
20Pathogenic Variants
FUNCTIONAL ROLE
Transcription Factor
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
DNA-binding transcription activator activity, RNA polymerase II-specificnucleoplasmregulation of actin cytoskeleton organizationprotein bindingvan der Woude syndromecleft palateisolated cleft palategenetic disorder
✦AI Summary

GRHL3 is a transcription factor that binds the consensus DNA sequence 5'-AACCGGTT-3' to function as both an activator and repressor of target genes 12. In normal physiology, GRHL3 is essential for epidermal barrier formation and neural tube closure, with functional redundancy with GRHL2 in epidermal wound repair 3. GRHL3 expression is induced during epidermal differentiation through glucose-dependent mechanisms involving the IRF6 transcription factor 4 and DDX21-mediated mRNA splicing 5, where it activates pro-differentiation genes including TGM3. In disease contexts, GRHL3 plays complex and sometimes contradictory roles. In cancer, GRHL3 overexpression promotes epithelial-mesenchymal transition and invasion through E-cadherin repression in colorectal and breast cancers 67, and mediates hepatocellular carcinoma metastasis via the GPX4/PTEN/PI3K/AKT axis 8. Conversely, GRHL3 restricts APOBEC3A expression to differentiated cells, preventing mutagenic activity during DNA replication, though this restriction is lost in squamous cell carcinoma 9. GRHL3 also supports triple-negative breast cancer angiogenesis through HIF1A/VEGFA signaling 10 and may inhibit T cell-mediated anti-tumor immunity by regulating RNF114 11. These findings underscore GRHL3's context-dependent roles in development, homeostasis, and malignancy.

Sources cited
1
GRHL3 binds DNA sequence 5'-AACCGGTT-3' as activator and repressor
PMID: 21081122
2
GRHL3 binds DNA consensus sequence and regulates gene expression
PMID: 25347468
3
GRHL3 required for oral periderm development
PMID: 24360809
4
Glucose modulates IRF6 to induce GRHL3 during epidermal differentiation
PMID: 40120584
5
DDX21-glucose interaction promotes GRHL3 mRNA splicing in differentiation
PMID: 36608661
6
GRHL3 promotes epithelial tumor migration/invasion via E-cadherin downregulation
PMID: 26837418
7
GRHL3 knockdown inhibits colorectal cancer cell proliferation and induces apoptosis
PMID: 29270747
8
GPX4 silences GRHL3 to activate PI3K/AKT pathway in HCC metastasis
PMID: 38797432
9
GRHL3 restricts APOBEC3A expression to differentiated cells; restriction lost in squamous cell carcinoma
PMID: 39548236
10
STAMBPL1 upregulates GRHL3 to activate HIF1A/VEGFA axis in breast cancer angiogenesis
PMID: 40208233
11
PIEZO1 upregulates GRHL3 to induce RNF114, reducing T cell cytotoxicity
PMID: 38514773
Disease Associationsβ“˜21
van der Woude syndromeOpen Targets
0.77Strong
cleft palateOpen Targets
0.61Moderate
isolated cleft palateOpen Targets
0.53Moderate
genetic disorderOpen Targets
0.49Moderate
van der Woude syndrome 1Open Targets
0.44Moderate
cleft lipOpen Targets
0.38Weak
pyelonephritisOpen Targets
0.24Weak
hypertrophic cardiomyopathyOpen Targets
0.23Weak
neural tube defects, folate-sensitiveOpen Targets
0.11Weak
head and neck squamous cell carcinomaOpen Targets
0.09Suggestive
Isolated anencephaly/exencephalyOpen Targets
0.09Suggestive
anencephaly 1Open Targets
0.09Suggestive
Spina bifida - hypospadiasOpen Targets
0.08Suggestive
spina bifida-hypospadias syndromeOpen Targets
0.08Suggestive
colorectal carcinomaOpen Targets
0.08Suggestive
strokeOpen Targets
0.07Suggestive
neoplasmOpen Targets
0.07Suggestive
spina bifidaOpen Targets
0.06Suggestive
cancerOpen Targets
0.06Suggestive
urinary bladder carcinomaOpen Targets
0.06Suggestive
Van der Woude syndrome 2UniProt
Pathogenic Variants20
NM_198173.3(GRHL3):c.1171C>T (p.Arg391Cys)Pathogenic
Van der Woude syndrome 2|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 391
NM_198173.3(GRHL3):c.1047+1G>APathogenic
Inborn genetic diseases
β˜…β˜†β˜†β˜†2025
NM_198173.3(GRHL3):c.934C>T (p.Gln312Ter)Pathogenic
Inborn genetic diseases
β˜…β˜†β˜†β˜†2023β†’ Residue 312
NM_198173.3(GRHL3):c.134_152dup (p.Asn51fs)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2022β†’ Residue 51
NM_198173.3(GRHL3):c.318dup (p.Thr107fs)Likely pathogenic
Van der Woude syndrome 2
β˜…β˜†β˜†β˜†2022β†’ Residue 107
NM_198173.3(GRHL3):c.204+2T>CLikely pathogenic
Van der Woude syndrome 2
β˜…β˜†β˜†β˜†2022
NM_198173.3(GRHL3):c.1419+1G>APathogenic
Van der Woude syndrome 2
β˜…β˜†β˜†β˜†2020
NM_198173.3(GRHL3):c.899G>A (p.Trp300Ter)Pathogenic
Van der Woude syndrome 2
β˜…β˜†β˜†β˜†2017β†’ Residue 300
NM_198173.3(GRHL3):c.1285+2delPathogenic
Isolated cleft palate
β˜…β˜†β˜†β˜†2015
NM_198173.3(GRHL3):c.916dup (p.Arg306fs)Pathogenic
Isolated cleft palate
β˜…β˜†β˜†β˜†2015β†’ Residue 306
NM_198173.3(GRHL3):c.840+1G>TPathogenic
Isolated cleft palate
β˜…β˜†β˜†β˜†2015
NM_198173.3(GRHL3):c.1795C>G (p.Leu599Val)Likely pathogenic
Inborn genetic diseases
β˜…β˜†β˜†β˜†2014β†’ Residue 599
NM_198173.3(GRHL3):c.1115del (p.Leu372fs)Likely pathogenic
Van der Woude syndrome 2
β˜…β˜†β˜†β˜†β†’ Residue 372
NM_198173.3(GRHL3):c.847del (p.Val282_Val283insTer)Likely pathogenic
GRHL3-related disorder
β˜†β˜†β˜†β˜†2024β†’ Residue 282
NM_198173.3(GRHL3):c.22A>G (p.Arg8Gly)Likely pathogenic
Isolated cleft palate
β˜†β˜†β˜†β˜†2021β†’ Residue 8
NM_198173.3(GRHL3):c.1172G>A (p.Arg391His)Pathogenic
Isolated cleft palate
β˜†β˜†β˜†β˜†2021β†’ Residue 391
NM_198173.3(GRHL3):c.1563_1566del (p.Glu522fs)Pathogenic
Van der Woude syndrome 2
β˜†β˜†β˜†β˜†2014β†’ Residue 522
NM_198173.3(GRHL3):c.1419+1G>TPathogenic
Van der Woude syndrome 2
β˜†β˜†β˜†β˜†2014
NM_198173.3(GRHL3):c.893G>A (p.Arg298His)Pathogenic
Van der Woude syndrome 2
β˜†β˜†β˜†β˜†2014β†’ Residue 298
NM_198173.3(GRHL3):c.970_971insGT (p.Phe324fs)Pathogenic
Van der Woude syndrome 2
β˜†β˜†β˜†β˜†2014β†’ Residue 324
View on ClinVar β†—
Related Genes
IRF6Protein interaction83%TGM1Protein interaction79%ZNF750Protein interaction74%LCE7AShared pathway20%KPLCEShared pathway20%HRNRShared pathway20%
Tissue Expression6 tissues
Brain
100%
Liver
72%
Bone Marrow
49%
Heart
19%
Ovary
14%
Lung
9%
Gene Interaction Network
Click a node to explore
GRHL3IRF6TGM1ZNF750LCE7AKPLCEHRNR
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted Β· UniProt Q8TE85
View on AlphaFold β†—
Constraintβ“˜
LOEUFβ“˜
0.40Moderately Constrained
pLIβ“˜
1.00Intolerant
Observed/Expected LoF0.26 [0.17–0.40]
RankingsWhere GRHL3 stands among ~20K protein-coding genes
  • #8,320of 20,598
    Most Researched54
  • #2,200of 5,498
    Most Pathogenic Variants20
  • #2,011of 17,882
    Most Constrained (LOEUF)0.40 Β· top quartile
Genes detectedGRHL3
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
PIEZO1 mechanically regulates the antitumour cytotoxicity of T lymphocytes.
PMID: 38514773
Nat Biomed Eng Β· 2024
1.00
2
Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation.
PMID: 36608661
Cell Β· 2023
0.90
3
Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation.
PMID: 40120584
Cell Stem Cell Β· 2025
0.80
4
Grhl3 induces human epithelial tumor cell migration and invasion via downregulation of E-cadherin.
PMID: 26837418
Acta Biochim Biophys Sin (Shanghai) Β· 2016
0.70
5
GPX4 transcriptionally promotes liver cancer metastasis via GRHL3/PTEN/PI3K/AKT axis.
PMID: 38797432
Transl Res Β· 2024
0.60