Affinage

SIX4

Homeobox protein SIX4 · UniProt Q9UIU6

Length
781 aa
Mass
82.9 kDa
Annotated
2026-06-10
57 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIX4 is a homeodomain transcription factor that binds MEF3/Trex DNA elements through its homeodomain and transactivates muscle-specific target genes via a C-terminal transactivation domain (PMID:8628654, PMID:14966291). Acting redundantly with its paralog Six1, SIX4 sits at the top of the developmental hierarchy that establishes skeletal muscle, kidney, gonad, and olfactory placode lineages: in Six1/Six4 double-null mice, Pax3 and the myogenic regulatory factors Myogenin, Myod1, and Mrf4 fail to be expressed and myogenic cells fail to delaminate and migrate (PMID:15788460), Gdnf and ureteric bud formation are lost in the metanephric mesenchyme (PMID:17300925), the olfactory placode fails to form (PMID:19027001), and male sex determination fails through loss of Sry activation downstream of Fog2 and Nr5a1 (PMID:23987514). Mechanistically, SIX4 cooperates genome-wide with MyoD and Pax3, co-occupying muscle gene loci and increasing chromatin accessibility, and its synergy with MyoD is coupled to removal of the repressive H3K27me3 mark by the demethylase Utx (PMID:26229056, PMID:27302134, PMID:30807574); SIX4 transcription is itself directly driven by MyoD binding E-box/MEF3 sites in the SIX4 promoter, creating a feedforward loop (PMID:29307818). SIX4 functions with cofactors of the Eyes absent family, interacting directly with EYA3 during myogenesis (PMID:38026174). Beyond development, SIX4 acts as a pro-tumorigenic and pro-inflammatory transcription factor: it binds the promoters of YAP1 and MET to drive hepatocellular carcinoma metastasis within an HGF feedback loop (PMID:33046796), physically interacts with STAT3 to promote its nuclear translocation and EMT (PMID:32064163), directly transcribes STING to shape anti-tumor immunity (PMID:37888903), and participates in an IL-6/STAT3/SIX4/c-Jun feedback loop while inducing DeltaNp63 in colorectal contexts (PMID:39309424).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 Medium

    Establishing that SIX4 is a sequence-specific DNA-binding transactivator answered whether it acts directly on gene regulatory elements rather than as an accessory factor.

    Evidence GAL4-fusion reporter assays, DNA-binding to the Na,K-ATPase ARE element, and subcellular fractionation in C2C12 myoblasts

    PMID:8628654

    Open questions at the time
    • Physiological target genes not yet defined
    • Dual nuclear/cytoplasmic localization and processed forms not mechanistically explained
  2. 2004 High

    Identifying SIX4 as the Trex/MEF3-binding factor in the MCK enhancer connected its DNA-binding activity to a defined muscle-specific regulatory grammar.

    Evidence Oligonucleotide-affinity proteomics, gel-shift with Six-specific antisera, and reporter assays on MCK, Aldolase A, and Cardiac troponin C elements

    PMID:14966291

    Open questions at the time
    • Distinction of Six4 vs Six5 roles across tissues incomplete
    • Cofactor requirements for transactivation not resolved
  3. 2005 High

    Double-knockout genetics placed Six1/Six4 upstream of the core myogenic transcription factors and distinguished their target specificity from Six1.

    Evidence Six1/Six4 double-KO mouse genetics with in situ markers (Pax3, Myogenin, Myod1, Mrf4) and EMSA on the Slc12a2 promoter

    PMID:15788460 PMID:15955062

    Open questions at the time
    • Direct vs indirect regulation of each myogenic factor not separated
    • Redundancy boundaries between Six1 and Six4 unquantified
  4. 2006 Medium

    Drosophila genetics established a deeply conserved role for Six4/Eya in mesodermal and gonadal cell-fate specification.

    Evidence Loss- and gain-of-function genetics, misexpression with Eyes absent cofactor, and tin epistasis in fly embryos

    PMID:16595131 PMID:17517128

    Open questions at the time
    • Direct transcriptional targets in fly not mapped
    • Relationship to vertebrate target sets unclear
  5. 2007 High

    Extending the Six1/Six4 requirement to kidney and olfactory placode showed SIX4 operates as a master upstream regulator across multiple organ primordia.

    Evidence Six1/Six4 double-KO mice with marker analysis of Gdnf, Pax2/Pax8 (kidney) and Eya2/Sox2 (olfactory placode)

    PMID:17300925 PMID:19027001

    Open questions at the time
    • Whether SIX4 binds these target promoters directly not shown
    • Signaling integration (Fgf/Bmp) downstream vs upstream unresolved
  6. 2013 High

    Defining the Fog2 and Nr5a1 branches downstream of Six1/Six4 explained how these factors control both Sry activation and gonadal precursor growth in sex determination.

    Evidence Double-KO mouse genetics with Sry transgenic rescue and expression analysis of Fog2 and Nr5a1

    PMID:23987514

    Open questions at the time
    • Direct SIX4 occupancy at Fog2/Nr5a1 loci not demonstrated
    • Mechanism limiting rescue of precursor cell growth unknown
  7. 2016 High

    Genome-wide co-occupancy with MyoD, Pax3, and Utx, plus a self-promoter loop, revealed how SIX4 mechanistically drives the myogenic program through chromatin remodeling and feedforward circuitry.

    Evidence ChIP-seq of Six4/MyoD/Utx and Pax3, ATAC-seq, MEF reprogramming assays, EMSA/ChIP on the SIX4 promoter, and in vivo regeneration RNAi

    PMID:26229056 PMID:27302134 PMID:29307818 PMID:30807574

    Open questions at the time
    • Direct recruitment mechanism of Utx by SIX4 not established
    • Quantitative contribution of each cofactor (Mef2, Pbx-Meis, EBF) unresolved
  8. 2020 Medium

    Satellite cell analysis clarified that SIX4 is required for proper positioning and functional competence of muscle stem cells, beyond initial lineage specification.

    Evidence Six1/Six4 double-KO PAX7+ cell quantification, transcriptome, and transplantation into regenerating muscle

    PMID:32591430

    Open questions at the time
    • Transcriptional targets governing satellite cell positioning unmapped
    • Cell-autonomous vs niche contributions not fully separated
  9. 2023 Medium

    Identifying EYA3 as a primary SIX4 partner and a Drosophila trimeric complex defined the cofactor architecture through which SIX4 regulates differentiation.

    Evidence Mass spectrometry of the EYA3 interactome with transcriptomics in myogenesis, and genetic/complex analysis of Six4-Earmuff-PntP1 in fly neuroblasts

    PMID:33556050 PMID:38026174

    Open questions at the time
    • Structural basis of SIX4-EYA3 interaction unknown
    • Whether neuroblast and myogenic cofactor logic is shared unclear
  10. 2024 Medium

    Multiple cancer studies established SIX4 as a pro-tumorigenic transcription factor acting through STAT3, YAP1/MET, STING, and IL-6/c-Jun circuits.

    Evidence ChIP/reporter assays on YAP1, MET, STING, c-Jun, and DeltaNp63 promoters; Co-IP with STAT3; CRISPR KO/rescue and in vivo tumor and inflammation models

    PMID:32064163 PMID:33046796 PMID:37888903 PMID:39309424

    Open questions at the time
    • Whether oncogenic targets share the MEF3 binding grammar of developmental targets unclear
    • Most cancer findings rest on single-lab studies without reciprocal validation
  11. 2025 Medium

    Drug-modifier screening linked SIX4 to CDK8/Mediator-kinase-dependent transcriptional rewiring in rhabdomyosarcoma, connecting its myogenic activity to therapeutic vulnerability.

    Evidence Genome-scale CRISPR screen with CDK8 inhibition and transcriptional profiling (preprint)

    PMID:bio_10.1101_2025.07.14.663986

    Open questions at the time
    • Preprint not peer-reviewed
    • Direct SIX4-Mediator interaction not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single MEF3-binding homeodomain factor selects developmental versus oncogenic target gene sets, and which cofactors and chromatin states toggle that selection, remains unresolved.
  • No structural model of SIX4 on DNA with EYA cofactors
  • Rules governing context-specific target choice unknown
  • Direct in vivo binding at most cancer targets not validated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 7 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1643685 Disease 4
Partners
C-JUNEYA3MYODPAX3STAT3UTX

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 SIX4 (AREC3) protein contains a homeodomain required for specific DNA binding to the ARE (Na,K-ATPase alpha1 subunit gene regulatory element), and a transactivation domain in the C-terminal region identified by GAL4-fusion reporter assays. The protein localizes to both nucleus and cytoplasm of myoblast C2C12 cells, with the 115 kDa form increased in cytoplasmic extract and the 67 kDa form increased in both nuclear and cytoplasmic extracts during muscle differentiation. Reporter gene assays with GAL4-AREC3 fusion constructs, immunohistochemistry, Western blot analysis of nuclear and cytoplasmic fractions during differentiation Nucleic acids research Medium 8628654
2004 SIX4 is the transcriptional regulatory element X (Trex)-binding factor (TrexBF) in the Muscle Creatine Kinase (MCK) enhancer in mouse skeletal myocytes and embryonic day 10 chick skeletal and cardiac muscle. SIX4 transactivates the MCK enhancer as well as muscle-specific regulatory regions of Aldolase A and Cardiac troponin C via Trex/MEF3 sites. In adult mouse heart, Six5 (not Six4) is the major TrexBF. Quantitative proteomics of oligonucleotide-affinity-purified proteins, gel shift assays, Six-specific antisera, cotransfection reporter assays Molecular and cellular biology High 14966291
2005 In Six1/Six4 double knockout mice, Pax3 expression is impaired in limb bud somitic cells, blocking myogenic cell delamination and migration; within the myotome, myogenin, Myod1 and Mrf4 expression are abolished, and Myf5 becomes restricted to the caudal somite region, placing Six1 and Six4 upstream of these myogenic regulatory factors. Double knockout mouse genetics, in situ hybridization, immunohistochemistry for myogenic markers Development (Cambridge, England) High 15788460
2005 Six1 and Six4 differentially regulate a set of target genes. The promoter of Slc12a2 (NKCC1) contains multiple Six1-binding sites and one common binding site for both Six1 and Six4 by gel-retardation assay, indicating distinct DNA-binding specificities. In vivo, Slc12a2 expression is reduced in the dorsal root ganglia of Six1/Six4 double-null mice. Gel-retardation assays (EMSA), target gene screening, in situ hybridization in double-KO mice The FEBS journal Medium 15955062
2006 In Drosophila, D-Six4 is required for development of non-dorsal mesodermal cell types (fat body, somatic gonadal cells, specific somatic muscles). Misexpression analysis shows D-Six4 and its cofactor Eyes absent are sufficient to impose these fates on other mesodermal cells. Tinman (tin) function is required for full D-six4 expression at stage 9. Loss-of-function genetics, misexpression analysis, epistasis between tin and D-six4 Developmental biology Medium 16595131
2007 Six1 and Six4 cooperate in the metanephric mesenchyme to regulate Gdnf expression; Six1/Six4 double-null mice lack ureteric bud formation and show complete absence of Pax2, Pax8, and Gdnf expression in metanephric mesenchyme, whereas Six1 deficiency alone only partially reduces these markers. Double knockout mouse genetics, in situ hybridization, molecular marker analysis Mechanisms of development High 17300925
2007 In Drosophila, Six4 is required in somatic gonadal precursors (SGPs) for expression of Hmgcr (HMG-CoA reductase), which is necessary for attraction of primordial germ cells (PGCs) to SGPs. Six4 affects male-specific SGP migration by a different (Hmgcr-independent) pathway. SGPs also fail to coalesce into unified gonads without functional Six4. Live time-lapse fluorescence imaging of wild-type and mutant embryos, in vivo genetic analysis, epistasis with Hmgcr BMC developmental biology Medium 17517128
2008 Six1 and Six4 are required synergistically for olfactory placode formation; embryos lacking both Six1 and Six4 fail to form the olfactory placode despite normal specification of the preplacodal region (marked by Eya2). Six1 and Six4 act at the top of events controlling olfactory placode specification and patterning through Fgf and Bmp signaling pathways. Double knockout mouse genetics, in situ hybridization, molecular marker analysis (Eya2, Mash1, Sox2) Developmental biology Medium 19027001
2013 Six1 and Six4 homeoproteins are required together for male sex determination: double loss leads to male-to-female sex reversal in XY mice due to failure of Sry activation. Forced Sry transgene expression rescues testicular development but not precursor cell growth. Two downstream pathways are identified: Six1/Six4 regulate Fog2 (Zfpm2) to induce Sry expression, and regulate Nr5a1 (Ad4BP/Sf1) to control gonadal precursor formation. Double knockout mouse genetics, transgenic rescue with Sry, in situ hybridization and gene expression analysis of Fog2 and Nr5a1 Developmental cell High 23987514
2015 During adult skeletal muscle regeneration, Six4 co-occupies a core set of muscle gene loci genome-wide together with MyoD and the histone H3K27me3 demethylase Utx. Six4 and MyoD cooperation is associated with removal of the H3K27me3 repressive chromatin mark. In vivo RNAi of Six4 reveals an uncompensated function in muscle regeneration. ChIP-seq (genome-wide occupancy of Six4, MyoD, Utx), in vivo RNAi knockdown with muscle regeneration phenotype FASEB journal High 26229056
2016 Six1 or Six4 are required for MyoD-mediated reprogramming of mouse embryonic fibroblasts toward myogenesis. Genome-wide analysis identified >700 genes co-regulated by Six and MyoD, with MyoD ChIP-seq data showing co-localization of MyoD and MEF3 (Six-binding) sites at >1000 genomic regions. The Six/MyoD synergistic activation involves a feedforward mechanism recruiting Mef2, Pbx-Meis, and EBF co-factors. Microarray expression profiling, MyoD ChIP-seq, genome-wide MEF3 site search, luciferase reporter assays for individual CRMs, MEF reprogramming assay Nucleic acids research High 27302134
2019 SIX4 directly binds to the promoters of YAP1 and MET (c-MET) to transactivate their expression in hepatocellular carcinoma cells. HGF upregulates SIX4 expression through the ERK/NF-κB pathway, forming a positive feedback loop (HGF→SIX4→c-MET). Knockdown of both YAP1 and c-MET inhibits SIX4-mediated HCC metastasis. ChIP assay (SIX4 binding to YAP1 and MET promoters), luciferase reporter assays, rescue experiments with YAP1/c-MET knockdown and overexpression, ERK/NF-κB pathway inhibition Oncogene Medium 33046796
2019 SIX4 increases expression of VEGF-A by coordinating with HIF-1α, and upregulates HIF-1α expression in an Akt-dependent manner, thereby promoting tumor angiogenesis in colorectal cancer cells. Overexpression and knockdown of SIX4, in vitro angiogenesis assay, Western blot for HIF-1α/Akt/VEGF-A, in vivo tumor growth assay Experimental cell research Low 31301290
2019 SIX4 directly interacts with STAT3 protein and promotes phosphorylated STAT3 nuclear translocation, thereby inducing EMT program activation (via Snai1 induction) and breast cancer metastasis. Co-immunoprecipitation (SIX4-STAT3 interaction), knockdown/overexpression with migration/invasion assays, in vivo lung metastasis assay American journal of cancer research Medium 32064163
2019 SIX4 chromatin co-occupancy with Pax3 is demonstrated genome-wide in mesodermal cells. Pax3 cooperates with Six4 (and Tead2) factors and involves chromatin remodeling (increased chromatin accessibility at bound elements) to activate the skeletal myogenic lineage. ATAC-seq (chromatin accessibility), ChIP-seq (Pax3 binding), transcriptome profiling in Pax3-induced ESCs and Pax3-null embryos PLoS biology Medium 30807574
2020 In Six1/Six4 double knockout mice, fewer PAX7+ satellite cells occupy their normal position at E18; the remaining mutant PAX7+ cells can divide and contribute to muscle growth but form hypotrophic, non-innervated myofibers after transplantation and retain self-renewal capacity. Double knockout mouse genetics, immunofluorescence for PAX7+ cell counting, transcriptome analysis, transplantation assay in adult regenerating muscle Development (Cambridge, England) Medium 32591430
2021 In Drosophila type II neuroblast lineages, Six4 prevents supernumerary type II neuroblasts and premature INP differentiation. Six4 inhibits the expression and activity of PntP1 in immature INPs (imINPs) in part by forming a trimeric complex with Earmuff and PntP1. Six4 also prevents premature differentiation by suppressing ectopic Prospero expression in imINPs. Loss-of-function genetics (six4 mutants), genetic epistasis with pntP1 and earmuff, complex formation demonstrated PLoS genetics Medium 33556050
2023 SIX4 directly transcribes STING (cGAS/STING pathway) in colon cancer cells: SIX4 knockout decreases STING mRNA and protein, ectopic SIX4 increases STING expression, and reexpression of SIX4 or STING in SIX4 KO cells reverses the effect. SIX4 depletion attenuates STING activation and downstream signaling, and reduces CD8+ T cell tumor infiltration and anti-PD-1 efficacy in vivo. CRISPR knockout and ectopic expression of SIX4, qPCR/Western blot for STING levels, STING activation assays (DMXAA/cGAMP), in vivo tumor immunology experiments Cancer research communications Medium 37888903
2023 EYA3 isoforms (regulated by RBFOX2-controlled alternative splicing) interact with SIX4 as a major transcription factor partner during myogenesis. Mass spectrometry-based proteomics and genome-wide transcriptomics identified SIX4 as a primary EYA3-interacting protein that dictates gene expression during muscle cell differentiation. Mass spectrometry proteomics (EYA3 interactome), genome-wide transcriptomic analysis, myoblast proliferation/differentiation assays iScience Medium 38026174
2023 MKRN2 interacts with STAT1 (shown by Co-IP), and MKRN2 regulates SIX4 expression via the EBF2 transcription factor in mouse testis and MEF cells; loss of MKRN2 significantly decreases SIX4 expression. MKRN2 knockout mouse model, Co-IP (MKRN2-STAT1 interaction), expression analysis of SIX4 in KO testis Frontiers in endocrinology Low 36967804
2024 SIX4 is transcriptionally activated by the IL-6/STAT3 signaling pathway in colorectal epithelium, and activated SIX4 binds to c-Jun to transcribe IL-6, forming a positive IL-6/STAT3/SIX4/c-Jun feedback loop that drives intestinal inflammation. SIX4 also binds the DeltaNp63 promoter (but not wild-type p63) to induce tumor stemness signaling. ChIP assay (SIX4 binding to c-Jun and DeltaNp63 promoters), reporter assays, in vivo DSS/AOM-DSS mouse models, siRNA knockdown International journal of biological sciences Medium 39309424
2025 In alveolar rhabdomyosarcoma, SIX4 is identified as a key transcription factor that mediates CDK8 inhibitor-induced transcriptional activation of myogenic differentiation genes and tumor cell proliferation. The maximal anti-tumor activity of CDK8 inhibitors requires the Mediator kinase module and transcriptional cooperation with the SAGA complex. Genome-scale CRISPR-Cas9 drug modifier screen, CDK8 knockout and pharmacologic inhibition, transcriptional profiling, in vitro and in vivo tumor models bioRxivpreprint Medium bio_10.1101_2025.07.14.663986
2018 MyoD binds directly at MyoD and E-box recognition sites in the core promoter region (-522/-193) of bovine SIX4, as demonstrated by EMSA and ChIP; site-directed mutagenesis and siRNA interference confirm that MyoD regulates SIX4 transcription through both direct and indirect mechanisms. EMSA, chromatin immunoprecipitation (ChIP), luciferase reporter assays with 5'-deletion constructs, site-directed mutation, siRNA knockdown of MyoD Biochemical and biophysical research communications Medium 29307818
2022 FOXA1 directly regulates SIX4 transcription in cervical cancer; FOXA1 binds the SIX4 promoter as demonstrated by ChIP and dual-luciferase assay. SIX4 overexpression promotes phosphorylation of PI3K and AKT, activating the PI3K/AKT signaling pathway, and reverses FOXA1 knockdown effects on cell growth and chemoresistance. ChIP assay, dual-luciferase reporter assay (FOXA1 binding SIX4 promoter), siRNA knockdown, PI3K/AKT Western blot Analytical cellular pathology (Amsterdam) Medium 35498155

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo. Development (Cambridge, England) 249 15788460
1996 Structure, function and expression of a murine homeobox protein AREC3, a homologue of Drosophila sine oculis gene product, and implication in development. Nucleic acids research 108 8628654
2001 Six4, a putative myogenin gene regulator, is not essential for mouse embryonal development. Molecular and cellular biology 100 11313460
2016 microRNA-309 targets the Homeobox gene SIX4 and controls ovarian development in the mosquito Aedes aegypti. Proceedings of the National Academy of Sciences of the United States of America 97 27489347
2008 Initiation of olfactory placode development and neurogenesis is blocked in mice lacking both Six1 and Six4. Developmental biology 79 19027001
2013 Homeoproteins Six1 and Six4 regulate male sex determination and mouse gonadal development. Developmental cell 77 23987514
2007 Six1 and Six4 are essential for Gdnf expression in the metanephric mesenchyme and ureteric bud formation, while Six1 deficiency alone causes mesonephric-tubule defects. Mechanisms of development 76 17300925
2000 Expression of three zebrafish Six4 genes in the cranial sensory placodes and the developing somites. Mechanisms of development 74 11044620
2006 Six1 and Six4 promote survival of sensory neurons during early trigeminal gangliogenesis. Brain research 63 16938278
2004 Quantitative proteomic identification of six4 as the trex-binding factor in the muscle creatine kinase enhancer. Molecular and cellular biology 60 14966291
2020 Effect of lncRNA WT1-AS regulating WT1 on oxidative stress injury and apoptosis of neurons in Alzheimer's disease via inhibition of the miR-375/SIX4 axis. Aging 47 33234729
2006 D-six4 plays a key role in patterning cell identities deriving from the Drosophila mesoderm. Developmental biology 45 16595131
2020 SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET. Oncogene 42 33046796
2005 Slc12a2 is a direct target of two closely related homeobox proteins, Six1 and Six4. The FEBS journal 34 15955062
2017 SIX4 promotes metastasis via activation of the PI3K-AKT pathway in colorectal cancer. PeerJ 30 28584719
2015 Genome-wide association between Six4, MyoD, and the histone demethylase Utx during myogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29 26229056
2020 Circular RNA-hsa-circ-0000670 promotes gastric cancer progression through the microRNA-384/SIX4 axis. Experimental cell research 28 32535033
2019 Time-dependent Pax3-mediated chromatin remodeling and cooperation with Six4 and Tead2 specify the skeletal myogenic lineage in developing mesoderm. PLoS biology 27 30807574
2018 MiR-203a functions as a tumor suppressor in bladder cancer by targeting SIX4. Neoplasma 26 30509104
2016 MyoD reprogramming requires Six1 and Six4 homeoproteins: genome-wide cis-regulatory module analysis. Nucleic acids research 26 27302134
2020 SIX4 promotes metastasis through STAT3 activation in breast cancer. American journal of cancer research 25 32064163
2019 SIX4 activates Akt and promotes tumor angiogenesis. Experimental cell research 25 31301290
2018 Polymorphism in promoter of SIX4 gene shows association with its transcription and body measurement traits in Qinchuan cattle. Gene 20 29496553
2007 Live imaging of Drosophila gonad formation reveals roles for Six4 in regulating germline and somatic cell migration. BMC developmental biology 20 17517128
1998 A zebrafish Six4 homologue with early expression in head mesoderm. Biochimica et biophysica acta 20 9805006
2019 SIX4 acts as a master regulator of oncogenes that promotes tumorigenesis in non-small-cell lung cancer cells. Biochemical and biophysical research communications 19 31266633
2014 Novel polymorphisms of SIX4 gene and their association with body measurement traits in Qinchuan cattle. Gene 18 24462757
2010 Insect Tc-six4 marks a unit with similarity to vertebrate placodes. Developmental biology 18 21034730
2019 MiRNA-621 inhibits the malignant progression of non-small cell lung cancer via targeting SIX4. European review for medical and pharmacological sciences 17 31210312
2024 Hinokiflavone exerts dual regulation on apoptosis and pyroptosis via the SIX4/Stat3/Akt pathway to alleviate APAP-induced liver injury. Life sciences 16 39147316
2021 Homeodomain protein Six4 prevents the generation of supernumerary Drosophila type II neuroblasts and premature differentiation of intermediate neural progenitors. PLoS genetics 16 33556050
2019 miR-802 inhibits the proliferation, invasion, and epithelial-mesenchymal transition of glioblastoma multiforme cells by directly targeting SIX4. Cell biochemistry and function 15 31702057
1998 Localization of Six4/AREC3 in the developing mouse retina; implications in mammalian retinal development. Experimental eye research 15 9990334
1999 Structure and chromosome mapping of the human SIX4 and murine Six4 genes. Cytogenetics and cell genetics 12 10640827
2023 SIX4 upregulates IDH1 and metabolic reprogramming to promote osteosarcoma progression. Journal of cellular and molecular medicine 11 36601689
2022 Silencing of SiX-4 enhances the chemosensitivity of melanoma cells to Cisplatin. Pathology, research and practice 11 36370483
2011 Development of gustatory papillae in the absence of Six1 and Six4. Journal of anatomy 11 21978088
2019 Disabling of nephrogenesis in porcine embryos via CRISPR/Cas9-mediated SIX1 and SIX4 gene targeting. Xenotransplantation 10 30623494
2010 Expression of Six1 and Six4 in mouse taste buds. Journal of molecular histology 10 20668922
2021 Upregulation of SIX4 indicates poor clinical outcome and promotes tumor growth and cell metastasis in esophageal squamous cell carcinoma. Thoracic cancer 9 33481352
2020 SIX1 and SIX4 homeoproteins regulate PAX7+ progenitor cell properties during fetal epaxial myogenesis. Development (Cambridge, England) 9 32591430
2023 SIX4 Controls Anti-PD-1 Efficacy by Regulating STING Expression. Cancer research communications 8 37888903
2023 Resveratrol suppresses NSCLC cell growth, invasion and migration by mediating Wnt/β-catenin pathway via downregulating SIX4 and SPHK2. Journal of chemotherapy (Florence, Italy) 8 37968995
2022 FOXA1 Leads to Aberrant Expression of SIX4 Affecting Cervical Cancer Cell Growth and Chemoresistance. Analytical cellular pathology (Amsterdam) 8 35498155
2022 IGF2BP3‑stabilized SIX4 promotes the proliferation, migration, invasion and tube formation of ovarian cancer cells. Molecular medicine reports 8 35616130
2023 Knockdown of SIX4 inhibits pancreatic cancer cells via apoptosis induction. Medical oncology (Northwood, London, England) 7 37656231
2023 RBFOX2 regulated EYA3 isoforms partner with SIX4 or ZBTB1 to control transcription during myogenesis. iScience 7 38026174
2018 Characterization of the promoter region of bovine SIX4: Roles of E-box and MyoD in the regulation of basal transcription. Biochemical and biophysical research communications 7 29307818
2016 Low Six4 and Six5 gene dosage improves dystrophic phenotype and prolongs life span of mdx mice. Development, growth & differentiation 6 27224259
2024 miR-540-3p partially recovers the locomotor function of spinal cord injury mice by targeting SIX4/Yap1 and inactivation of astrocytes. Neurological research 4 38920017
2024 SIX4 Activation in Inflammatory Response Drives the Transformation of Colorectal Epithelium into Inflammation and Tumor via Feedback-Enhancing Inflammatory Signaling to Induce Tumor Stemness Signaling. International journal of biological sciences 4 39309424
2023 MKRN2 knockout causes male infertility through decreasing STAT1, SIX4, and TNC expression. Frontiers in endocrinology 3 36967804
2023 Combination of SIX4-siRNA and temozolomide inhibits the growth and migration of A-172 glioblastoma cancer cells. Naunyn-Schmiedeberg's archives of pharmacology 3 37093251
2025 Molecular characterization and in silico analysis of 'secreted in xylem 4' (Six4) gene from Fusarium oxysporum infecting Pisum sativum. Archives of microbiology 1 41175167
2023 SIX4, a potential therapeutic target for estrogen receptor-positive breast cancer patients, is associated with low promoter methylation level. Epigenomics 1 37905439
2026 Association of baPWV and CD34+ progenitor-derived exosomal hsa_circ_0093884 with Alzheimer's disease: mechanistic insights into the miR-375/SIX4 axis. Frontiers in cell and developmental biology 0 42222331
2025 Generation of six4 -nlsRFP: a red somatic gonadal nuclear marker for live imaging Drosophila gonadogenesis. microPublication biology 0 40672113

Missed literature

Know a paper Affinage missed for SIX4? Flag it for the maintainers and the community.

No submissions yet.