Affinage

SIX4

Homeobox protein SIX4 · UniProt Q9UIU6

Length
781 aa
Mass
82.9 kDa
Annotated
2026-04-28
56 papers in source corpus 23 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIX4 is a homeodomain transcription factor that binds MEF3/Trex DNA elements through its Six domain and homeodomain to activate muscle-specific and developmental gene programs. SIX4 transactivates the muscle creatine kinase enhancer, Aldolase A, and cardiac troponin C promoters via MEF3 sites, and cooperates genome-wide with MyoD, the H3K27 demethylase Utx, Pax3, and EYA3 to remodel chromatin and drive skeletal myogenic lineage specification and muscle regeneration (PMID:14966291, PMID:26229056, PMID:30807574, PMID:38026174). Acting synergistically with Six1, SIX4 is required for Pax3 expression and myogenic regulatory factor activation in the somite, for Gdnf-dependent kidney induction, for olfactory placode formation, and for Sry-driven male sex determination (PMID:15788460, PMID:17300925, PMID:19027001, PMID:23987514). In cancer contexts, SIX4 directly transactivates YAP1, MET, and STING promoters, physically interacts with STAT3 to promote its nuclear translocation, and participates in an IL-6/STAT3/SIX4/c-Jun positive feedback loop driving inflammation and metastasis (PMID:33046796, PMID:32064163, PMID:37888903, PMID:39309424).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 High

    Establishing SIX4 as a DNA-binding transcription factor with a C-terminal transactivation domain resolved the basic molecular identity of the protein and showed it is upregulated during myoblast differentiation.

    Evidence DNA binding assays, GAL4-fusion reporter assays, immunohistochemistry in C2C12 myoblasts

    PMID:8628654

    Open questions at the time
    • Endogenous target genes not identified
    • In vivo function unknown
    • Cofactor requirements undefined
  2. 2004 High

    Identification of SIX4 as the MEF3/Trex-binding factor on the MCK enhancer established its direct transcriptional targets in skeletal and cardiac muscle, answering which genes SIX4 activates.

    Evidence Quantitative proteomics with oligonucleotide affinity purification, gel shift with Six-specific antisera, cotransfection reporter assays in myocytes

    PMID:14966291

    Open questions at the time
    • Whether SIX4 is sufficient or requires cofactors for MCK activation in vivo
    • Genome-wide target repertoire unknown
  3. 2005 High

    Genetic double knockout of Six1 and Six4 revealed their synergistic requirement for Pax3 expression and myogenic cell migration from the somite, placing them atop the transcriptional hierarchy of skeletal myogenesis and defining their cooperative rather than redundant roles.

    Evidence Six1/Six4 double knockout mice with in situ hybridization and immunostaining; differential DNA-binding specificity shown by EMSA for Slc12a2 promoter

    PMID:15788460 PMID:15955062

    Open questions at the time
    • Individual Six4 contribution difficult to separate from Six1 in double KO
    • Direct binding to Pax3 regulatory elements not demonstrated
  4. 2007 High

    Extension of the Six1/Six4 double knockout analysis to kidney and gonad development showed that their synergy controls Gdnf in metanephric mesenchyme and Hmgcr in Drosophila somatic gonadal precursors, broadening SIX4's role beyond muscle to organogenesis and germ cell biology.

    Evidence Six1/Six4 double KO mice (kidney agenesis), Drosophila Six4 loss-of-function with live imaging (gonad)

    PMID:17300925 PMID:17517128

    Open questions at the time
    • Direct Six4 binding to Gdnf regulatory regions not shown
    • Conservation of gonadal mechanism between fly and mammal not established
  5. 2008 High

    The demonstration that Six1/Six4 double knockout abolishes olfactory placode formation via Fgf and Bmp pathways established SIX4 as a pan-sensory developmental regulator, not restricted to mesodermal fates.

    Evidence Six1/Six4 double KO mice, gene expression and cell proliferation/apoptosis analysis

    PMID:19027001

    Open questions at the time
    • Direct SIX4 binding at olfactory-specific enhancers not mapped
    • Six4-only contribution not separated
  6. 2013 High

    Showing that Six1/Six4 are required for Sry expression through Fog2 and Nr5a1 resolved how this transcription factor pair controls mammalian sex determination upstream of the male-determining switch.

    Evidence Six1/Six4 double KO with Sry transgene rescue, gene expression analysis

    PMID:23987514

    Open questions at the time
    • Whether SIX4 binds Sry regulatory elements directly or acts through Fog2/Nr5a1 intermediaries
  7. 2015 High

    Genome-wide ChIP-seq revealed that SIX4 co-localizes with MyoD and the Utx demethylase at regulatory regions where it promotes H3K27me3 removal, providing the first epigenomic mechanism for SIX4's transcriptional activation function and showing a non-redundant role in adult muscle regeneration.

    Evidence ChIP-seq in myogenic cells, in vivo RNAi during muscle regeneration, chromatin mark analysis

    PMID:26229056

    Open questions at the time
    • Whether SIX4 directly recruits Utx or their co-binding is independent
    • Structural basis of SIX4-MyoD cooperation unknown
  8. 2016 High

    Demonstrating that Six4 (or Six1) is required for MyoD-mediated fibroblast-to-myocyte reprogramming, with feedforward recruitment of Mef2, Pbx-Meis, and EBF, established SIX4 as an essential chromatin-opening pioneer partner for myogenic conversion.

    Evidence MEF reprogramming assay, MyoD ChIP-seq, genome-wide MEF3 site analysis, luciferase reporters

    PMID:27302134

    Open questions at the time
    • Pioneer factor activity of SIX4 itself not directly tested
    • Relative contribution of Six4 vs Six1 in reprogramming not resolved
  9. 2019 High

    Integration of ATAC-seq and ChIP-seq showing Pax3 and SIX4 co-binding at newly accessible chromatin sites during myogenic specification linked SIX4 to chromatin remodeling at Hedgehog, Notch, and BMP pathway loci and established cooperative chromatin opening as a conserved mechanism in mouse and human.

    Evidence ATAC-seq, ChIP-seq, transcriptome profiling in Pax3-null embryos and Pax3-induced ES cells

    PMID:30807574

    Open questions at the time
    • Temporal order of Pax3 vs SIX4 binding not resolved
    • Whether SIX4 is required for Pax3-mediated accessibility or vice versa
  10. 2020 Medium

    Discovery that SIX4 directly transactivates YAP1 and MET promoters and interacts with STAT3 to promote its nuclear translocation revealed oncogenic functions in hepatocellular carcinoma and breast cancer metastasis, extending SIX4 biology beyond developmental myogenesis.

    Evidence ChIP and promoter-binding assays, Co-IP for SIX4-STAT3, knockdown/overexpression with in vivo metastasis models

    PMID:32064163 PMID:33046796

    Open questions at the time
    • Whether SIX4 binds STAT3 directly or through bridging factors not fully resolved
    • SIX4 cancer functions studied in single labs without independent replication
    • Whether developmental and oncogenic targets overlap is unknown
  11. 2023 Medium

    Identification of SIX4 as a principal regulator of STING expression linked SIX4 to innate immune signaling in colon cancer, with SIX4 knockout attenuating cGAS/STING signaling and CD8+ T cell infiltration, revealing an immune-modulatory function.

    Evidence CRISPR knockout and ectopic overexpression, STING pathway assays, in vivo anti-PD-1 experiments

    PMID:37888903

    Open questions at the time
    • Direct SIX4 binding to STING promoter not demonstrated by ChIP in this study
    • Generalizability beyond colon cancer unknown
  12. 2023 Medium

    Mass spectrometry identification of EYA3 isoforms as major SIX4 interaction partners during myogenesis, with RBFOX2-regulated alternative splicing of Eya3 exon 7 determining complex composition, provided a mechanism for combinatorial control of SIX4 transcriptional output.

    Evidence Mass spectrometry-based proteomics, genome-wide transcriptomics, RNA immunoprecipitation in myoblasts

    PMID:38026174

    Open questions at the time
    • Structural basis of SIX4-EYA3 isoform selectivity unknown
    • Whether EYA3 phosphatase activity is required for SIX4 function not tested
  13. 2024 Medium

    Demonstration of an IL-6/STAT3/SIX4/c-Jun positive feedback loop driving intestinal inflammation, with SIX4 binding c-Jun to transcribe IL-6 and separately activating the DeltaNp63 promoter for tumor stemness, expanded SIX4's role to inflammatory signaling and cancer stemness.

    Evidence ChIP assay, promoter binding, DSS/AOM mouse models, siRNA knockdown

    PMID:39309424

    Open questions at the time
    • Whether SIX4-c-Jun interaction is direct or bridged is not fully established
    • Relationship between inflammatory and stemness functions of SIX4 not delineated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether SIX4 has genuine pioneer factor activity independent of Pax3/MyoD, the structural basis of SIX4's interactions with its diverse protein partners (STAT3, c-Jun, EYA3, Utx), and how developmental versus oncogenic target gene selection is determined.
  • No structural data (crystal/cryo-EM) for SIX4 in complex with any partner
  • Six4-specific (vs Six1-redundant) function in most developmental contexts not isolated by single KO
  • Genome-wide SIX4 binding in cancer contexts not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 2
Partners
EYA3JUNKDM6AMYOD1PAX3SIX1STAT3

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 SIX4 (AREC3) binds specifically to the ARE (Na,K-ATPase alpha1 subunit gene regulatory element) DNA sequence via its homeodomain, and contains a transactivation domain in its C-terminal region identified by GAL4-fusion reporter assays. The protein localizes to both nucleus and cytoplasm of myoblast C2C12 cells and is upregulated during muscle differentiation. DNA binding assays, GAL4 fusion transactivation reporter assays, immunohistochemistry, Western blot Nucleic acids research High 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 chick skeletal/cardiac muscle. SIX4 transactivates the MCK enhancer and muscle-specific regulatory regions of Aldolase A and Cardiac troponin C via Trex/MEF3 sites. Quantitative proteomics with oligonucleotide-coupled magnetic bead enrichment, gel shift assays, Six-specific antisera, cotransfection transactivation assays Molecular and cellular biology High 14966291
2005 Six1 and Six4 are required together for Pax3 gene expression, which controls myogenic cell delamination and migration from the somite into limb buds. In the myotome, absence of Six1 and Six4 impairs expression of myogenic regulatory factors myogenin, Myod1, and Mrf4, while Myf5 becomes restricted to the caudal somite region. Six1/Six4 double knockout mice, in situ hybridization, immunostaining, apoptosis assays Development (Cambridge, England) High 15788460
2005 Six1 and Six4 differentially regulate common target genes due to distinct DNA-binding specificities; the Slc12a2 (sodium-potassium-chloride cotransporter 1) promoter contains multiple Six1-binding sites and one common Six1/Six4 binding site, and Slc12a2 expression is reduced in dorsal root ganglia of Six1/Six4 double-knockout mice. Gel-retardation (EMSA) assays, in situ hybridization in knockout mice The FEBS journal High 15955062
2007 Six1 and Six4 cooperate in the metanephric mesenchyme to regulate Gdnf expression; Six1/Six4 double-deficient mice fail to express Pax2, Pax8, or Gdnf in metanephric mesenchyme, resulting in absence of ureteric bud and kidney/ureter agenesis. Six4 alone cooperates with Six1 in the metanephros but not the mesonephros. Six1/Six4 double knockout mice, immunostaining, in situ hybridization Mechanisms of development High 17300925
2008 Six1 and Six4 function synergistically at the top of the transcriptional hierarchy controlling olfactory placode formation and neuronal development; embryos lacking both Six1 and Six4 fail to form the olfactory placode, acting through Fgf and Bmp signaling pathways. Six1/Six4 double knockout mice, gene expression analysis, in situ hybridization, cell proliferation and apoptosis assays Developmental biology High 19027001
2013 Six1 and Six4 are required together for male sex determination by activating Sry expression; they regulate two downstream targets: Fog2 (Zfpm2), which induces Sry expression for male sex determination, and Nr5a1 (Ad4BP/Sf1), which controls gonadal precursor formation and gonadal size. Six1/Six4 double knockout mice, Sry transgene rescue, gene expression analysis Developmental cell High 23987514
2015 Six4 cooperates genome-wide with MyoD and the histone H3K27me3 demethylase Utx during adult skeletal myogenesis; Six4 binding at regulatory regions is associated with removal of repressive chromatin marks, and Six4 in vivo RNAi reveals an uncompensated function during muscle regeneration. ChIP-seq, genome-wide binding analysis, RNA interference in vivo, chromatin mark analysis FASEB journal High 26229056
2016 Six1 or Six4 are required for MyoD-mediated reprogramming of mouse embryonic fibroblasts to myogenic fate; Six4 and MyoD binding sites co-localize genome-wide, and their synergistic transcriptional activation involves feedforward recruitment together with partner transcription factors including Mef2, Pbx-Meis, and EBF. Microarray expression profiling, MyoD ChIP-seq, genome-wide MEF3 binding site analysis, luciferase reporter assays, MEF reprogramming assay Nucleic acids research High 27302134
2019 Pax3 cooperates with Six4 (and Tead2) to remodel chromatin at target loci during skeletal myogenic lineage specification; Pax3 binding increases chromatin accessibility at elements that are also bound by Six4, linking Six4 to Hedgehog, Notch, and BMP signaling pathway activation in myogenesis. ATAC-seq (chromatin accessibility), ChIP-seq, transcriptome profiling of Pax3-null embryos and Pax3-induced ES cells, mouse and human systems PLoS biology High 30807574
2020 SIX4 promotes hepatocellular carcinoma metastasis by directly binding the promoters of YAP1 and MET proto-oncogene to transactivate their expression. HGF upregulates SIX4 via ERK/NF-κB pathway, forming a positive feedback loop. Knockdown of YAP1 and c-MET inhibits SIX4-mediated HCC metastasis. Promoter binding assays, gene knockdown/overexpression, invasion/migration assays, in vivo metastasis models, ChIP Oncogene Medium 33046796
2020 SIX4 promotes breast cancer metastasis by directly interacting with STAT3 protein and promoting phosphorylated STAT3 nuclear translocation, thereby inducing Snai1 expression and EMT program activation. Co-immunoprecipitation, knockdown/overexpression, migration/invasion assays, in vivo lung metastasis model American journal of cancer research Medium 32064163
2019 SIX4 upregulates HIF-1α expression through Akt activation, which in turn increases VEGF-A expression to promote tumor angiogenesis in colorectal cancer. Gene overexpression/knockdown, in vitro tube formation assays, in vivo tumor growth assays, Western blot for pathway components Experimental cell research Low 31301290
2023 SIX4 is a principal regulator of STING expression in colon cancer cells; SIX4 knockout decreases STING mRNA and protein levels and attenuates downstream cGAS/STING signaling, while ectopic SIX4 expression increases STING expression and enhances STING agonist-induced signaling. Decreased SIX4 reduces CD8+ T cell tumor infiltration and anti-PD-1 efficacy in vivo. CRISPR knockout, ectopic overexpression, STING pathway signaling assays, in vivo immune checkpoint blockade experiments Cancer research communications Medium 37888903
2023 EYA3 isoforms interact with SIX4 (and ZBTB1) as major transcription factor partners during myogenesis, with alternative splicing of Eya3 exon 7 (regulated by RBFOX2) determining which transcription factor complex forms to dictate gene expression during muscle cell differentiation. Mass spectrometry-based proteomics, genome-wide transcriptomics, RNA immunoprecipitation, myoblast differentiation assays iScience Medium 38026174
2021 In Drosophila type II neuroblast lineages, Six4 prevents dedifferentiation of immature intermediate neural progenitors (imINPs) by forming a trimeric complex with Earmuff and PntP1, thereby inhibiting PntP1 expression and activity and preventing premature differentiation via suppression of ectopic Prospero expression. Drosophila genetics (loss-of-function), epistasis analysis, immunostaining, clonal analysis PLoS genetics Medium 33556050
2007 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 to SGPs; Six4 also controls msSGP migration via a distinct Hmgcr-independent pathway, and is required for coalescence of SGP clusters. Live time-lapse fluorescence imaging, Drosophila genetics (loss-of-function), in situ hybridization BMC developmental biology Medium 17517128
2018 MyoD regulates bovine SIX4 transcription by binding to MyoD recognition sites and E-box elements in the core promoter region (-522/-193), acting through both direct and indirect mechanisms at these sites. 5' deletion luciferase reporter assays, EMSA, ChIP assay, site-directed mutagenesis, siRNA interference Biochemical and biophysical research communications Medium 29307818
1999 Human SIX4 gene maps to chromosome 14q23; the gene structure including the 5' upstream region is well conserved between human and mouse. Genomic cloning, chromosome mapping Cytogenetics and cell genetics Medium 10640827
2024 SIX4, transcriptionally activated by the IL-6/STAT3 signaling pathway, binds to c-Jun to transcribe IL-6, forming a positive IL-6/STAT3/SIX4/c-Jun feedback loop that drives intestinal inflammation. Additionally, SIX4 directly binds the DeltaNp63 promoter (not wild-type p63) to induce tumor stemness signals in colorectal cancer. ChIP assay, promoter binding assays, in vivo DSS/AOM mouse models, siRNA knockdown, gene expression analysis International journal of biological sciences Medium 39309424
2022 FOXA1 transcriptionally regulates SIX4 expression in cervical cancer; ChIP and dual-luciferase assays validated FOXA1 as a direct upstream transcriptional regulator of SIX4, and SIX4 in turn activates the PI3K/AKT signaling pathway. ChIP assay, dual-luciferase reporter assay, gene knockdown/overexpression, PI3K/AKT pathway analysis Analytical cellular pathology (Amsterdam) Medium 35498155
2023 MKRN2 interacts with STAT1 (demonstrated by Co-IP) and regulates SIX4 expression via EBF2 transcription factor in mouse testis; loss of Mkrn2 decreases SIX4 expression and causes male infertility. Mkrn2 knockout mice, Co-IP assay, Western blot, gene expression analysis Frontiers in endocrinology Low 36967804
2020 SIX4 PAX7+ progenitor cells in Six1/Six4 double knockout mice are fewer in satellite cell position at E18, but retained PAX7+ cells can still divide and contribute to muscle growth; transplantation reveals mutant stem cells form hypotrophic, non-innervated myofibers but retain self-renewal capacity. Six1/Six4 double knockout mice, immunostaining, transcriptome analysis, satellite cell transplantation assay Development (Cambridge, England) Medium 32591430
2024 SIX1, SIX2, and SIX4 (with SIX1 and SIX2 most critical) are necessary for induction of DUX4 transcription in differentiating FSHD myotubes; DUX4 in turn downregulates SIX RNA levels, suggesting a negative feedback loop. siRNA knockdown in FSHD myotubes, gene expression analysis bioRxivpreprint Low
2025 SIX4 is a key transcription factor mediating CDK8 inhibitor-induced transcriptional activation of myogenic differentiation genes in alveolar rhabdomyosarcoma; identified through genome-scale CRISPR-Cas9 drug modifier screen. Genome-scale CRISPR-Cas9 drug modifier screen, CDK8 knockout/inhibition, transcriptional analysis bioRxivpreprint Low

Source papers

Stage 0 corpus · 56 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) 245 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 107 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 96 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 46 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 41 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 26 30807574
2018 MiR-203a functions as a tumor suppressor in bladder cancer by targeting SIX4. Neoplasma 26 30509104
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
2016 MyoD reprogramming requires Six1 and Six4 homeoproteins: genome-wide cis-regulatory module analysis. Nucleic acids research 25 27302134
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
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
2024 Hinokiflavone exerts dual regulation on apoptosis and pyroptosis via the SIX4/Stat3/Akt pathway to alleviate APAP-induced liver injury. Life sciences 14 39147316
2021 Homeodomain protein Six4 prevents the generation of supernumerary Drosophila type II neuroblasts and premature differentiation of intermediate neural progenitors. PLoS genetics 14 33556050
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
2011 Development of gustatory papillae in the absence of Six1 and Six4. Journal of anatomy 11 21978088
2022 Silencing of SiX-4 enhances the chemosensitivity of melanoma cells to Cisplatin. Pathology, research and practice 10 36370483
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
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
2022 IGF2BP3‑stabilized SIX4 promotes the proliferation, migration, invasion and tube formation of ovarian cancer cells. Molecular medicine reports 7 35616130
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 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
2024 miR-540-3p partially recovers the locomotor function of spinal cord injury mice by targeting SIX4/Yap1 and inactivation of astrocytes. Neurological research 3 38920017
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
2023 SIX4, a potential therapeutic target for estrogen receptor-positive breast cancer patients, is associated with low promoter methylation level. Epigenomics 1 37905439
2025 Generation of six4 -nlsRFP: a red somatic gonadal nuclear marker for live imaging Drosophila gonadogenesis. microPublication biology 0 40672113
2025 Molecular characterization and in silico analysis of 'secreted in xylem 4' (Six4) gene from Fusarium oxysporum infecting Pisum sativum. Archives of microbiology 0 41175167