Affinage

SIX1

Homeobox protein SIX1 · UniProt Q15475

Length
284 aa
Mass
32.2 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIX1 is a homeodomain transcription factor that orchestrates precursor-cell proliferation and differentiation programs across mammalian organogenesis, acting as the DNA-binding component of a bipartite complex with EYA co-factors whose phosphatase activity converts the SIX1-DACH complex from a repressor to an activator (PMID:14628042). Productive transcription requires both an intact Six-domain interaction with EYA—which stabilizes SIX1, enhances its DNA-binding affinity, and drives nuclear localization—and a functional homeodomain for sequence-specific DNA recognition; mutations in either module cause branchio-oto-renal syndrome through these two distinct biochemical lesions (PMID:15141091, PMID:19497856). SIX1 recognizes MEF3 and related sites, with the homeodomain conferring core discrimination and flanking domains broadening the binding spectrum (PMID:22730291). In development, SIX1 operates within EYA-dependent regulatory hierarchies that sit downstream of PAX3 and upstream of effectors including Pax2/Six2/Sall1 and Grem1 in kidney branching morphogenesis (PMID:12783782, PMID:21281623, PMID:11262400), MyoD/myogenin and Dusp6 in myogenesis and satellite-cell differentiation (PMID:12668636, PMID:22945933, PMID:23840772, PMID:27302134), Fgf8 within a Tbx1 craniofacial/cardiovascular pathway (PMID:21364285), and Sry/Fog2/Nr5a1 in male sex determination (PMID:23987514). SIX1 also engages chromatin machinery directly, partnering with the SWI/SNF subunits BRG1 and BAF170 (whose ATPase activity is required for SIX1/EYA-driven neurogenesis) and with SOX2 (PMID:22513373), and cooperating with Polycomb complexes to repress p16INK4A-mediated senescence (PMID:26500063). When re-activated in cancer, SIX1 redeploys these programs: it directly induces TβRI to activate TGF-β signaling and EMT (PMID:21056993), drives VEGF-C-dependent lymphangiogenesis and metastasis (PMID:22466647), reprograms metabolism by transactivating glycolytic genes via the HBO1/AIB1 acetyltransferases and LDHA (PMID:29455928, PMID:36937004), suppresses p53 through a miR-27a/RPL26 axis (PMID:26687066), and shapes an immunosuppressive collagen-rich microenvironment via TGFBR2-Smad2/3 (PMID:34782761). SIX1 protein levels are gated post-translationally by CK2 phosphorylation that reduces mitotic DNA binding (PMID:10801845), APC/Cdh1-mediated proteolysis (PMID:17130831), stabilizing O-GlcNAcylation at T276 that blocks ubiquitination (PMID:32863962), and a GRP75-USP1 deubiquitinase complex that opposes K48-linked degradation (PMID:34079090). The SIX1/EYA2 interaction is pharmacologically tractable, with a small molecule disrupting the complex and reversing SIX1-driven EMT and metastasis (PMID:32341035).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Established that SIX1 DNA binding is not constitutive but cell-cycle-regulated, linking the transcription factor to mitotic control before its developmental partners were defined.

    Evidence In vitro CK2 kinase assay, cell-cycle synchronization, EMSA on the aldolase A promoter, and CK2 inhibitor treatment

    PMID:10801845

    Open questions at the time
    • Specific phosphorylated residues not mapped
    • Did not address how phosphorylation integrates with co-factor binding
  2. 2001 Medium

    Placed SIX1 within a myogenic hierarchy downstream of PAX3, answering where SIX1 acts in the genetic cascade that initiates skeletal muscle fate.

    Evidence Pax3 overexpression and dominant-negative in pluripotent stem cells with RT-PCR readout

    PMID:11262400

    Open questions at the time
    • No direct demonstration that PAX3 binds the Six1 locus
    • Single-lab epistasis without protein-level validation
  3. 2003 High

    Defined the central regulatory logic of the SIX1-EYA-DACH module: EYA phosphatase activity switches the complex from repression to activation, explaining how a single DNA-binding factor controls precursor proliferation.

    Evidence Genetic epistasis, co-activator recruitment and phosphatase activity assays, mouse knockouts

    PMID:14628042

    Open questions at the time
    • Direct dephosphorylation substrate of EYA in this switch not fully resolved
    • Generality across all SIX1 targets not established
  4. 2003 High

    Demonstrated organ-specific requirements for SIX1 in kidney and muscle, showing it acts upstream of distinct effector sets (Pax2/Six2/Sall1; MyoD/myogenin) downstream of Eya1.

    Evidence Six1 knockout mice with in situ hybridization and epistasis against Pax2, Eya1, Six2 knockouts; lacZ-replacement knockout with myogenic marker analysis

    PMID:12668636 PMID:12783782

    Open questions at the time
    • Which effector genes are direct vs indirect targets not all resolved
    • Did not define DNA-binding sites at effector loci
  5. 2004 High

    Showed SIX1+EYA1 co-expression is sufficient to reprogram muscle fiber type toward fast-twitch glycolytic identity, establishing SIX1 as an instructive driver of metabolic/contractile phenotype, and dissected the biochemical basis of BOR mutations.

    Evidence Transgenic gain-of-function in soleus with MyHC isoform analysis and MEF3 reporters; BOR mutation sequencing with EMSA and protein-interaction assays

    PMID:15141091 PMID:15226428

    Open questions at the time
    • Direct fast-twitch gene targets not all enumerated
    • Mechanism of nuclear accumulation preference not defined
  6. 2006 Medium

    Revealed cell-cycle-coupled destruction of SIX1 by APC/Cdh1 through a non-canonical degron, adding a degradation layer to SIX1's mitotic regulation.

    Evidence Cell-cycle synchronization, ubiquitin-proteolysis assays, Cdh1 Co-IP, and deletion mutants

    PMID:17130831

    Open questions at the time
    • Degron sequence not precisely defined
    • Single-lab mechanism without reciprocal in vivo confirmation
  7. 2009 High

    Resolved how EYA binding to the Six domain functionally enables SIX1, showing it stabilizes the protein, enhances DNA affinity, and promotes nuclear import—explaining why BOR Six-domain mutations are pathogenic.

    Evidence Recombinant protein reconstitution, interaction assays, luciferase reporters, nuclear localization studies, EMSA

    PMID:19497856

    Open questions at the time
    • Structural basis of the affinity enhancement not solved
    • In vivo relevance of each effect not separately tested
  8. 2010 High

    Identified TβRI as a direct SIX1 target that is necessary and sufficient to activate TGF-β signaling and EMT, defining a concrete molecular route from SIX1 reactivation to metastatic behavior.

    Evidence Gain/loss-of-function in breast cancer cells, TβRI knockdown rescue, TGF-β assays, in vivo metastasis

    PMID:21056993

    Open questions at the time
    • Direct promoter binding site not detailed here
    • Contribution relative to other EMT routes not quantified
  9. 2011 High

    Extended the SIX1/EYA regulatory network into developmental morphogenesis via direct Fgf8 control within a Tbx1 pathway and via Grem1-mediated antagonism of BMP4 in kidney branching.

    Evidence Mouse compound mutants, ChIP/target validation of Fgf8, GREM1 protein rescue and Bmp4 heterozygote epistasis

    PMID:21281623 PMID:21364285

    Open questions at the time
    • Direct vs indirect regulation of Grem1 not fully established
    • Tissue-specific co-factor requirements not defined
  10. 2012 High

    Connected SIX1 to chromatin-remodeling and angiogenic/cell-cycle programs, and refined its DNA-binding code—showing it physically engages SWI/SNF (BRG1/BAF170) and SOX2, directly drives VEGF-C and Dusp6, and recognizes a broader site spectrum than MEF3 alone.

    Evidence Reciprocal Co-IP with BRG1/BAF170 and ATPase-mutant epistasis; orthotopic xenograft with VEGF-C rescue; conditional satellite-cell knockout with Dusp6 ChIP; ChIP-seq with position-weight-matrix optimization

    PMID:22466647 PMID:22513373 PMID:22730291 PMID:22945933

    Open questions at the time
    • Whether SWI/SNF recruitment is direct at all SIX1 targets unknown
    • Stoichiometry of SIX1-SOX2-SWI/SNF complex undefined
  11. 2013 High

    Demonstrated direct SIX1 control of cyclin D1, MyoD enhancer activity, and the male sex-determination pathway, broadening the catalogue of direct targets and showing SIX1 shapes chromatin state at the MyoD Core Enhancer.

    Evidence Promoter-reporter and ChIP for cyclin D1 and MyoD enhancer with MEF3 mutagenesis; Six1/Six4 double knockout with Sry transgene rescue

    PMID:23527134 PMID:23840772 PMID:23987514

    Open questions at the time
    • Redundancy with SIX4 not resolved in all contexts
    • Mechanism of chromatin opening at MyoD enhancer not defined
  12. 2015 High

    Defined a p53-suppressing axis (miR-27a/RPL26, MDM2-independent) and identified a homeodomain hotspot mutation (Q177R) in blastemal Wilms tumors, linking SIX1 to tumor-suppressor evasion and cancer genetics.

    Evidence miRNA/RPL26 reporter and mutagenesis with SIX1 gain-of-function; exome/transcriptome sequencing of Wilms tumors with validation cohort

    PMID:25670083 PMID:26687066

    Open questions at the time
    • Functional mechanism of Q177R not established in the genomic study
    • Tissue specificity of the miR-27a/RPL26 axis untested
  13. 2016 High

    Established SIX1 as a feedforward partner of MyoD genome-wide and a direct regulator of fast-fiber/glycolytic and calcium-handling genes, unifying its developmental myogenic and metabolic roles.

    Evidence Microarray, MyoD ChIP-seq, genome-wide MEF3 search with reporter validation; conditional soleus deletion with transcriptomics and Parvalbumin ChIP

    PMID:27302134 PMID:27597886

    Open questions at the time
    • Direct vs cooperative occupancy at each module not always separable
    • SIX4 contribution to the metabolic program not isolated
  14. 2017 Medium

    Linked SIX1 transcriptional control of LDHA to lactate-driven metabolic and immune effects, an early connection between SIX1 metabolism and antitumor immunity.

    Evidence ChIP for the LDHA promoter, glycolysis assays, NK-cell co-culture

    PMID:36937004

    Open questions at the time
    • Single-lab study
    • Immune-evasion mechanism not validated in vivo here
  15. 2018 High

    Defined the mechanism of SIX1-driven Warburg metabolism, showing direct transactivation of glycolytic genes through the HBO1/AIB1 acetyltransferases and that a cancer mutation enhances this activity.

    Evidence Transcriptomics, ChIP-seq, gain/loss-of-function with HBO1/AIB1 epistasis, in vivo xenograft

    PMID:29455928

    Open questions at the time
    • Identity of the activating cancer mutation's structural effect not fully resolved
    • Relationship to LDHA axis not integrated
  16. 2020 High

    Identified a stabilizing O-GlcNAcylation at T276 and a druggable SIX1/EYA2 interface, defining new ways SIX1 levels are controlled and showing the complex is therapeutically targetable.

    Evidence Mass spectrometry, T276A mutagenesis, ubiquitination assays, tumor models; small-molecule screen disrupting SIX1/EYA2 with transcriptomic/metabolomic and in vivo metastasis readouts

    PMID:32341035 PMID:32863962

    Open questions at the time
    • O-GlcNAc transferase responsible for T276 not identified
    • Compound selectivity and in vivo pharmacology limited
  17. 2021 Medium

    Defined further post-translational stabilization (GRP75-USP1 deubiquitinase complex), a SOBP modulatory partner, Polycomb-cooperative senescence repression, and a collagen/TGFBR2-Smad2/3 immune-evasion mechanism, deepening SIX1's roles in protein homeostasis, plasticity, and the tumor microenvironment.

    Evidence Reciprocal Co-IP with domain mapping and K48-ubiquitination assays; Co-IP/co-localization and reporter assays with SOBP in Xenopus; fibroblast knockdown with Polycomb co-regulation; cancer-cell deletion with immune-competent tumor models

    PMID:26500063 PMID:34079090 PMID:34414417 PMID:34782761

    Open questions at the time
    • Each mechanism shown largely in single labs
    • How these layers are coordinated on the same SIX1 pool unknown
  18. 2022 High

    Showed SIX1 maintains the rhabdomyosarcoma undifferentiated state by directing enhancer activity and MYOD1 occupancy, demonstrating that SIX1 controls cell fate through genome-wide chromatin redistribution.

    Evidence Loss-of-function with ATAC-seq/ChIP-seq for enhancers, MYOD1/MYOG ChIP-seq, in vivo and zebrafish tumor assays

    PMID:35108532

    Open questions at the time
    • Co-factor(s) mediating enhancer selection not defined
    • Reversibility window for differentiation therapy not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple post-translational inputs (CK2 phosphorylation, APC/Cdh1 degradation, O-GlcNAcylation, GRP75-USP1 deubiquitination) are integrated to set SIX1 levels and activity within a single cell, and how SIX1 selects between developmental and oncogenic enhancer programs, remains unresolved.
  • No unified model linking PTM state to target-gene choice
  • Structural basis of SIX1-EYA-chromatin assembly not solved
  • Determinants of context-specific co-factor usage (SWI/SNF vs Polycomb vs HBO1/AIB1) unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 4
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-1430728 Metabolism 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
BAF170BRG1DACHEYA1EYA2GRP75SOBPSOX2
Complex memberships
GRP75-USP1-SIX1 complexSIX1-EYA-DACH transcription complexSWI/SNF (BRG1/BAF170)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 SIX1 forms a transcriptional complex with DACH and EYA factors; EYA phosphatase activity switches the SIX1-DACH complex from transcriptional repression to activation by recruiting co-activators, thereby regulating genes controlling precursor cell proliferation in mammalian organogenesis. Genetic epistasis, biochemical co-activator recruitment assays, phosphatase activity assays, in vivo mouse knockout Nature High 14628042
2004 SIX1 mutations causing branchio-oto-renal (BOR) syndrome disrupt the EYA1-SIX1-DNA ternary complex via two distinct mechanisms: the V17E (Six domain) mutation abolishes EYA1-SIX1 protein-protein interaction, while homeodomain mutations eliminate specific DNA binding by SIX1. Direct sequencing of BOR patients, recombinant protein expression and purification, protein-protein interaction assays, EMSA (electrophoretic mobility shift assay) Proceedings of the National Academy of Sciences of the United States of America High 15141091
2003 Six1 is required upstream of Pax2, Six2, and Sall1 expression in the metanephric mesenchyme for ureteric bud invasion; Eya1 functions upstream of Six1 in this developmental hierarchy. Six1 and Eya1 genetically interact during kidney development. Six1 knockout mice, in situ hybridization, epistasis analysis with Pax2, Eya1, Six2 knockouts Development (Cambridge, England) High 12783782
2003 Six1 loss in mice causes severe muscle hypoplasia by impairing primary myogenesis; Six1 plays a specific role in hypaxial muscle differentiation, with reduced MyoD and myogenin gene activation in limb buds by E11.5, without affecting myogenic precursor cell migration or apoptosis. Six1 knockout mice (lacZ replacement), immunostaining, gene expression analysis Development (Cambridge, England) High 12668636
2000 SIX1 is a nuclear phosphoprotein that undergoes hyperphosphorylation at mitosis by casein kinase II (CK2); CK2-mediated phosphorylation of SIX1 reduces its ability to bind MEF3 sites on the aldolase A promoter, and CK2 inhibition diminishes SIX1 phosphorylation and causes G2/M arrest. Cell cycle synchronization, in vitro kinase assay with recombinant SIX1 and CK2, EMSA, CK2 inhibitor (apigenin) treatment, immunoprecipitation The Journal of biological chemistry High 10801845
2004 Six1 and Eya1 co-expression in slow-twitch skeletal muscle is sufficient to reprogram adult slow-twitch oxidative fibers toward a fast-twitch glycolytic phenotype, driving fiber-type transition and activating fast-twitch fiber-specific genes; Six1 and Eya1 proteins preferentially accumulate in nuclei of fast-twitch muscles. Transgenic forced expression in slow-twitch soleus muscle, myosin heavy chain isoform analysis, nuclear fractionation, MEF3 promoter reporter assays Molecular and cellular biology High 15226428
2006 SIX1 protein is degraded during mitosis through ubiquitin-mediated proteolysis via the anaphase-promoting complex with Cdh1 (APC/Cdh1); unlike canonical APC/Cdh1 substrates, SIX1 lacks functional destruction or KEN box motifs—instead, its N- and C-terminal regions mediate degradation, and an N-terminal region directly binds Cdh1. Cell cycle synchronization, ubiquitin-mediated proteolysis assays, co-immunoprecipitation with Cdh1, deletion/mutant constructs Oncogene Medium 17130831
2009 SIX1 BOR syndrome mutations act through two distinct mechanisms: V17E in the Six domain abolishes SIX1-EYA complex formation and prevents EYA nuclear localization, while the remaining five homeodomain mutations are deficient in DNA binding. EYA interaction with the N-terminal Six domain increases SIX1 protein stability, enhances its DNA binding affinity, and promotes its nuclear localization. Recombinant protein expression/purification in E. coli, protein-protein interaction assays, luciferase reporter transcriptional assays, nuclear localization studies, EMSA The Journal of biological chemistry High 19497856
2012 EYA1 and SIX1 directly interact with SWI/SNF chromatin-remodeling subunits BRG1 and BAF170 to drive neuronal developmental programs; ATPase activity of BRG1 is required for EYA1/SIX1-induced ectopic neurogenesis. SOX2 cooperates with EYA1/SIX1 in this complex to mediate neuronal differentiation upstream of NEUROG1 and NEUROD1. Co-immunoprecipitation, overexpression in 3T3 fibroblasts and cochlear epithelial cells, BRG1 dominant-negative/mutant constructs, loss- and gain-of-function models Development (Cambridge, England) High 22513373
2012 SIX1 directly induces transcription of the prolymphangiogenic factor VEGF-C, which is required for SIX1-mediated peritumoral lymphangiogenesis and lymphatic metastasis of breast cancer cells in vivo. Overexpression/knockdown in human breast cancer cells, orthotopic xenograft mouse model, VEGF-C rescue/knockdown experiments, transcriptional reporter assays The Journal of clinical investigation High 22466647
2010 SIX1 directly upregulates TGF-β type I receptor (TβRI) expression, and this upregulation is both necessary and sufficient to activate TGF-β signaling and induce epithelial-to-mesenchymal transition (EMT) downstream of SIX1 in breast cancer cells. Gain/loss-of-function in breast cancer cell lines, TβRI knockdown rescue experiments, TGF-β signaling assays, in vivo metastasis models Cancer research High 21056993
2011 Six1 and Eya1 form a transcription complex that directly regulates Fgf8 as a downstream effector, and genetically interact with Tbx1 in a Tbx1-Six1/Eya1-Fgf8 pathway controlling cardiovascular and craniofacial development. Mouse compound mutants (Six1/Eya1 double knockouts), ChIP/direct target validation of Fgf8, genetic interaction with Tbx1 and Fgf8 heterozygotes The Journal of clinical investigation High 21364285
2012 Six1 regulates skeletal muscle satellite cell differentiation and controls the ERK1/2 pathway during regeneration through direct transcriptional control of Dusp6, a phosphatase that modulates ERK1/2 activity; loss of Six1 in satellite cells impairs differentiation and increases self-renewal. Conditional Six1 knockout in satellite cells, chromatin immunoprecipitation (ChIP) for Dusp6 locus, Dusp6 knockout analysis, regeneration assays The Journal of cell biology High 22945933
2013 Six1 directly transcriptionally activates cyclin D1 in pancreatic cancer cells; overexpression of Six1 upregulates cyclin D1 mRNA, protein, and cyclin D1 promoter activity, thereby promoting cell cycle progression and proliferation. Overexpression/knockdown, cyclin D1 promoter-luciferase reporter assays, in vivo xenograft PloS one Medium 23527134
2015 SIX1 decreases p53 levels through a dual mechanism: upregulation of microRNA-27a and downregulation of ribosomal protein L26 (RPL26), which acts as a competitive inhibitor of miR-27a-mediated p53 repression. This mechanism is MDM2-independent. Mutation analysis of RPL26 miRNA binding site, miRNA overexpression, RPL26 knockdown/overexpression, luciferase reporters, SIX1 gain-of-function Nature communications High 26687066
2013 Six1 binds the Core Enhancer Region of MyoD and is required for MyoD expression in satellite cells; Six1 also promotes proper chromatin structure at the Core Enhancer Region and MyoD binding at its own enhancer. ChIP assay, transcriptional reporter assays, RNA interference knockdown, site-directed mutagenesis of MEF3 binding sites PloS one High 23840772
2018 SIX1 directly increases the transcription of multiple glycolytic genes to promote the Warburg effect in cancer cells; this glycolytic function is mediated through the histone acetyltransferases HBO1 and AIB1. A cancer-related SIX1 mutation enhances its ability to promote aerobic glycolysis. Transcriptomics, ChIP-seq, gain/loss-of-function in cell lines and in vivo xenograft, HBO1/AIB1 co-factor knockdown epistasis Cancer cell High 29455928
2020 SIX1 undergoes O-GlcNAcylation at T276; this modification inhibits ubiquitination-mediated degradation of SIX1, thereby enhancing its protein stability and promoting hepatocellular carcinoma proliferation. T276A mutation decreases O-GlcNAcylation and reverses the pro-tumor effect. Mass spectrometry, immunoprecipitation, site-directed mutagenesis (T276A), O-GlcNAcylation and ubiquitination assays, in vitro and in vivo tumor models Theranostics High 32863962
2021 The molecular chaperone GRP75 maintains SIX1 protein stability by recruiting the deubiquitinase USP1, forming a GRP75-USP1-SIX1 complex that inhibits K48-linked polyubiquitination of SIX1; the C-terminus (433-679 aa) of GRP75 contains the peptide-binding domain required for complex formation. Co-immunoprecipitation, ubiquitination assays (K48-linked), domain mapping with truncation mutants, GRP75/USP1 knockdown/inhibition, xenograft models Oncogene High 34079090
2012 The DNA-binding sequence spectrum of SIX1 is broader than previously established; the Six1 homeodomain alone is sufficient for sequence discrimination, but domains outside the homeodomain also contribute to binding site selection. An optimized position weight matrix reveals MEF3-containing and novel binding sequences. ChIP-seq in myoblasts, biochemical binding assays (EMSA/pull-down), position weight matrix optimization algorithm Nucleic acids research Medium 22730291
2016 Six1 (and Six4) are required for MyoD-mediated reprogramming of mouse embryonic fibroblasts to myogenic fate; Six1/4 and MyoD co-occupy over 1000 genomic regions and synergistically activate 82 target genes through MEF3+E-box cis-regulatory modules in a feedforward regulatory mechanism. Microarray, MyoD ChIP-seq, genome-wide MEF3 site search, luciferase reporter assays for 19 cis-regulatory modules Nucleic acids research High 27302134
2022 SIX1 maintains the rhabdomyosarcoma undifferentiated state by controlling enhancer activity and MYOD1 occupancy at loci permissive for tumor growth over muscle differentiation; SIX1 loss induces MYOD1 and MYOG redistribution genome-wide, causing differentiation into myotube-like cells. SIX1 loss-of-function (knockdown/knockout), ATAC-seq/ChIP-seq for enhancer activity, MYOD1 and MYOG ChIP-seq, in vivo tumor growth assays, zebrafish model Cell reports High 35108532
2013 Six1 and Six4 together (but neither alone) are required for male sex determination by activating Sry expression through regulation of Fog2 (Zfpm2), and for gonadal precursor cell growth through regulation of Nr5a1 (Ad4BP/SF1). Six1/Six4 single and double knockout mice, epistasis with Sry transgene rescue, expression analysis of Fog2 and Nr5a1 Developmental cell High 23987514
2011 Six1 regulates Grem1 expression in the metanephric mesenchyme to control branching morphogenesis; in Six1-deficient kidneys, loss of Grem1 leads to unopposed BMP4 activity preventing ureteric bud ampulla formation, and both GREM1 protein rescue and Bmp4 heterozygosity restore kidney formation. Six1 knockout mice, GREM1 protein rescue experiments, Six1(-/-);Bmp4(+/-) compound mutants, expression analysis Developmental biology High 21281623
2015 The SIX1 homeodomain Q177R mutation (hotspot in Wilms tumors) occurs in the homeodomain and is associated with high proliferative potential in blastemal-type Wilms tumors, placing SIX1 mutations in a pathway with DROSHA/DGCR8 mutations in this cancer subtype. Exome and transcriptome sequencing of 58 blastemal-type Wilms tumors with validation cohort, functional validation of DROSHA mutants in cell lines Cancer cell Medium 25670083
2021 SIX1 promotes senescence repression through cooperation with Polycomb repressive complexes; SIX1 downregulation in fibroblasts triggers p16INK4A-mediated senescence. SIX1 also controls SOX2 expression to mediate cellular plasticity. SIX1 knockdown in human fibroblasts, transcriptomic analysis, Polycomb complex co-regulation analysis, glioma cell line functional assays Oncogene Medium 26500063
2021 SIX1 regulates expression of multiple collagen genes via TGFBR2-dependent Smad2/3 activation, promoting collagen deposition in the tumor microenvironment that impedes immune cell infiltration and antitumor immunity. Six1 deletion in cancer cells, in vivo tumor experiments with immune competent mice, collagen expression analysis, TGFBR2-Smad2/3 pathway activation assays Cellular & molecular immunology Medium 34782761
2017 SIX1 directly binds the promoter of the LDHA gene to transcriptionally regulate it, promoting lactate accumulation via the SIX1/LDHA axis in pancreatic cancer cells. Chromatin immunoprecipitation (ChIP) assay for LDHA promoter, glycolysis functional assays, co-culture with NK cells Journal of immunology research Medium 36937004
2021 Sobp directly binds SIX1 in the cell nucleus (co-immunoprecipitation and co-localization) and interferes with transcriptional activation of SIX1+EYA1 target genes, modulating Six1 transcriptional output during craniofacial development. Co-immunoprecipitation, immunofluorescence co-localization, luciferase reporter assays, Xenopus gain/loss-of-function Development (Cambridge, England) Medium 34414417
2020 A small molecule compound (NCGC00378430/8430) disrupts the SIX1/EYA2 protein-protein interaction, partially reverses SIX1-induced transcriptional and metabolic profiles, reverses TGFβ signaling and EMT, and suppresses breast cancer metastasis in vivo. Small molecule screen, SIX1/EYA2 interaction assay, transcriptomic/metabolomic profiling, in vivo metastasis model Cancer research Medium 32341035
2016 Six1 directly activates Parvalbumin (a key calcium buffer) as a direct transcriptional target in adult myofibers, and controls expression of fast-type sarcomeric proteins and glycolytic enzymes; deletion of Six1 in soleus leads to complete loss of MyHCIIA expression. Conditional Six1 deletion in soleus, global transcriptomics of isolated myofibers, ChIP for Parvalbumin locus Skeletal muscle Medium 27597886
2001 Pax3 is required upstream of SIX1 and EYA2 in skeletal myogenesis; forced expression of Pax3 induces Six1 and Eya2 expression prior to MyoD and myogenin, whereas a dominant-negative Pax3 abolishes Six1 and Eya2 expression and blocks myogenesis. Pax3 overexpression and dominant-negative in pluripotent stem cells, RT-PCR gene expression analysis The Journal of biological chemistry Medium 11262400

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 535 14628042
2018 Transcriptional Regulation of the Warburg Effect in Cancer by SIX1. Cancer cell 326 29455928
2004 SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proceedings of the National Academy of Sciences of the United States of America 306 15141091
2003 Six1 is required for the early organogenesis of mammalian kidney. Development (Cambridge, England) 287 12783782
2005 Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo. Development (Cambridge, England) 249 15788460
2015 Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors. Cancer cell 245 25670083
2003 Altered myogenesis in Six1-deficient mice. Development (Cambridge, England) 215 12668636
2004 Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes. Development (Cambridge, England) 195 15496442
2004 Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype. Molecular and cellular biology 162 15226428
2001 Pax3 is essential for skeletal myogenesis and the expression of Six1 and Eya2. The Journal of biological chemistry 122 11262400
2011 A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis. The Journal of clinical investigation 113 21364285
2012 SIX1 promotes epithelial-mesenchymal transition in colorectal cancer through ZEB1 activation. Oncogene 111 22286765
2000 Cell cycle-regulated phosphorylation of the human SIX1 homeodomain protein. The Journal of biological chemistry 111 10801845
2012 EYA1 and SIX1 drive the neuronal developmental program in cooperation with the SWI/SNF chromatin-remodeling complex and SOX2 in the mammalian inner ear. Development (Cambridge, England) 110 22513373
2012 SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer. The Journal of clinical investigation 108 22466647
2022 Exosomal lncRNA TUG1 from cancer-associated fibroblasts promotes liver cancer cell migration, invasion, and glycolysis by regulating the miR-524-5p/SIX1 axis. Cellular & molecular biology letters 106 35193488
2019 Circular RNA circNHSL1 promotes gastric cancer progression through the miR-1306-3p/SIX1/vimentin axis. Molecular cancer 103 31438963
2010 Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth. Cancer research 97 21056993
2008 Eya1 and Six1 promote neurogenesis in the cranial placodes in a SoxB1-dependent fashion. Developmental biology 89 18571637
2015 The SIX1-EYA transcriptional complex as a therapeutic target in cancer. Expert opinion on therapeutic targets 88 25555392
2014 Six1: a critical transcription factor in tumorigenesis. International journal of cancer 88 24488862
2012 Six1 regulates stem cell repair potential and self-renewal during skeletal muscle regeneration. The Journal of cell biology 88 22945933
2013 Six1 promotes proliferation of pancreatic cancer cells via upregulation of cyclin D1 expression. PloS one 84 23527134
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
2008 Expression of effector gene SIX1 of Fusarium oxysporum requires living plant cells. Fungal genetics and biology : FG & B 69 18606236
2017 Six1 promotes colorectal cancer growth and metastasis by stimulating angiogenesis and recruiting tumor-associated macrophages. Carcinogenesis 68 28199476
2009 Activation of Six1 target genes is required for sensory placode formation. Developmental biology 67 19781543
2004 Expression of zebrafish six1 during sensory organ development and myogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 67 15254912
2006 Six1 and Six4 promote survival of sensory neurons during early trigeminal gangliogenesis. Brain research 63 16938278
2011 Upregulation of notch2 and six1 is associated with progression of early-stage lung adenocarcinoma and a more aggressive phenotype at advanced stages. Clinical cancer research : an official journal of the American Association for Cancer Research 60 22190591
2010 Conserved expression of mouse Six1 in the pre-placodal region (PPR) and identification of an enhancer for the rostral PPR. Developmental biology 60 20471971
2020 O-GlcNAcylation of SIX1 enhances its stability and promotes Hepatocellular Carcinoma Proliferation. Theranostics 53 32863962
2015 The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. Nature communications 50 26687066
1996 Cloning of the human SIX1 gene and its assignment to chromosome 14. Genomics 47 8617500
2019 MiR-150-5p regulates melanoma proliferation, invasion and metastasis via SIX1-mediated Warburg Effect. Biochemical and biophysical research communications 44 31128917
2020 Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis. Cancer research 42 32341035
2015 MiR-204-5p/Six1 feedback loop promotes epithelial-mesenchymal transition in breast cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 42 26408179
2019 Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development. Journal of dental research 41 30905259
2019 miR-186-5p targeting SIX1 inhibits cisplatin resistance in non-small-cell lung cancer cells (NSCLCs). Neoplasma 41 31686523
2011 Expression and significance of Six1 and Ezrin in cervical cancer tissue. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 41 21874375
2020 MicroRNA-155-3p promotes glioma progression and temozolomide resistance by targeting Six1. Journal of cellular and molecular medicine 40 32220051
2020 Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4. Gut 40 32826305
2012 Regulation of Six1 expression by evolutionarily conserved enhancers in tetrapods. Developmental biology 40 22659139
2014 The role of Six1 in the genesis of muscle cell and skeletal muscle development. International journal of biological sciences 39 25210496
2014 HDAC5 promotes cell proliferation in human hepatocellular carcinoma by up-regulating Six1 expression. European review for medical and pharmacological sciences 38 24706304
2022 Ginsenoside Rh4 Suppresses Metastasis of Gastric Cancer via SIX1-Dependent TGF-β/Smad2/3 Signaling Pathway. Nutrients 37 35458126
2019 miR-140-5p induces cell apoptosis and decreases Warburg effect in chronic myeloid leukemia by targeting SIX1. Bioscience reports 37 30962263
2013 Six1 regulates MyoD expression in adult muscle progenitor cells. PloS one 37 23840772
2009 Biochemical and functional characterization of six SIX1 Branchio-oto-renal syndrome mutations. The Journal of biological chemistry 37 19497856
2022 SIX1 reprograms myogenic transcription factors to maintain the rhabdomyosarcoma undifferentiated state. Cell reports 36 35108532
2021 A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance. Oncogene 35 34079090
2016 The role of Six1 signaling in paclitaxel-dependent apoptosis in MCF-7 cell line. Bosnian journal of basic medical sciences 35 26773176
2010 Expression and clinical implications of homeobox gene Six1 in cervical cancer cell lines and cervical epithelial tissues. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 35 21370601
2006 Cell cycle regulation of the human Six1 homeoprotein is mediated by APC(Cdh1). Oncogene 35 17130831
2014 Six1 promotes epithelial-mesenchymal transition and malignant conversion in human papillomavirus type 16-immortalized human keratinocytes. Carcinogenesis 34 24574515
2011 Six1 and Eya1 are critical regulators of peri-cloacal mesenchymal progenitors during genitourinary tract development. Developmental biology 34 21968101
2017 Six1 is essential for differentiation and patterning of the mammalian auditory sensory epithelium. PLoS genetics 33 28892484
2019 miR-489-3p/SIX1 Axis Regulates Melanoma Proliferation and Glycolytic Potential. Molecular therapy oncolytics 32 32258386
2018 SIX1 and DACH1 influence the proliferation and apoptosis of hepatocellular carcinoma through regulating p53. Cancer biology & therapy 32 29333942
2020 Long Noncoding RNA XIST Contributes to Cervical Cancer Development Through Targeting miR-889-3p/SIX1 Axis. Cancer biotherapy & radiopharmaceuticals 30 32191528
2019 Regulation of cancer stem cell properties by SIX1, a member of the PAX-SIX-EYA-DACH network. Advances in cancer research 30 30691681
2019 LncRNA CRNDE promotes hepatocellular carcinoma progression by upregulating SIX1 through modulating miR-337-3p. Journal of cellular biochemistry 30 31099050
2017 Inhibition of Six1 affects tumour invasion and the expression of cancer stem cell markers in pancreatic cancer. BMC cancer 29 28388884
2023 The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer. Journal of immunology research 28 36937004
2021 SIX1 transcription factor: A review of cellular functions and regulatory dynamics. International journal of biological macromolecules 28 34742853
2012 Mutation screening of the EYA1, SIX1, and SIX5 genes in an East Asian cohort with branchio-oto-renal syndrome. The Laryngoscope 28 22447252
2012 EYA1-SIX1 complex in neurosensory cell fate induction in the mammalian inner ear. Hearing research 28 23104013
2011 Six1 regulates Grem1 expression in the metanephric mesenchyme to initiate branching morphogenesis. Developmental biology 28 21281623
2019 Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia. Cancer science 27 31050834
2000 A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred. American journal of human genetics 27 10777717
2016 MyoD reprogramming requires Six1 and Six4 homeoproteins: genome-wide cis-regulatory module analysis. Nucleic acids research 26 27302134
2016 Six1 homeoprotein drives myofiber type IIA specialization in soleus muscle. Skeletal muscle 25 27597886
2006 EYA1 and SIX1 gene mutations in Japanese patients with branchio-oto-renal (BOR) syndrome and related conditions. Pediatric nephrology (Berlin, Germany) 24 16491411
2022 SNS-023 sensitizes hepatocellular carcinoma to sorafenib by inducing degradation of cancer drivers SIX1 and RPS16. Acta pharmacologica Sinica 23 36261513
2012 Discovery, optimization and validation of an optimal DNA-binding sequence for the Six1 homeodomain transcription factor. Nucleic acids research 23 22730291
2011 A novel dominant mutation in SIX1, affecting a highly conserved residue, result in only auditory defects in humans. European journal of medical genetics 23 21700001
2023 SIX1 amplification modulates stemness and tumorigenesis in breast cancer. Journal of translational medicine 22 38031089
2015 Six1 promotes glioblastoma cell proliferation and invasion by upregulation of connective tissue growth factor. American journal of cancer research 22 26175950
2014 MicroRNA-30a regulates zebrafish myogenesis through targeting the transcription factor Six1. Journal of cell science 22 24634509
2022 Tanshinone IIA inhibits cell growth by suppressing SIX1-induced aerobic glycolysis in non-small cell lung cancer cells. Oncology letters 21 35527783
2022 circRNA PLOD2 promotes tumorigenesis and Warburg effect in colon cancer by the miR-513a-5p/SIX1/LDHA axis. Cell cycle (Georgetown, Tex.) 21 36071678
2020 FBXW7 promotes pathological cardiac hypertrophy by targeting EZH2-SIX1 signaling. Experimental cell research 21 32380038
2019 SIX1 represses senescence and promotes SOX2-mediated cellular plasticity during tumorigenesis. Scientific reports 21 30723235
2014 Targeting Six1 by lentivirus-mediated RNA interference inhibits colorectal cancer cell growth and invasion. International journal of clinical and experimental pathology 21 24551283
2014 Six1 is a key regulator of the developmental and evolutionary architecture of sensory neurons in craniates. BMC biology 21 24885223
2013 Core promoter analysis of porcine Six1 gene and its regulation of the promoter activity by CpG methylation. Gene 21 23954877
2013 Inhibition of Six1 promotes apoptosis, suppresses proliferation, and migration of osteosarcoma cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 21 24114014
2019 Increased Six1 expression in macrophages promotes hepatocellular carcinoma growth and invasion by regulating MMP-9. Journal of cellular and molecular medicine 20 31044528
2014 Immunohistochemical expression of homeoproteins Six1 and Pax3 in breast phyllodes tumours correlates with histological grade and clinical outcome. Histopathology 20 24438019
2023 LRRC75A-AS1 delivered by M2 macrophage exosomes promotes cervical cancer progression via enhancing SIX1 expression. Cancer science 19 36892427
2022 A SIX1 degradation inducer blocks excessive proliferation of prostate cancer. International journal of biological sciences 19 35414775
2021 Homeoprotein SIX1 compromises antitumor immunity through TGF-β-mediated regulation of collagens. Cellular & molecular immunology 19 34782761
2015 The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes. Oncogene 19 26500063
2022 Merkel Cell Carcinoma Sensitivity to EZH2 Inhibition Is Mediated by SIX1 Derepression. The Journal of investigative dermatology 18 35331717
2021 Sobp modulates the transcriptional activation of Six1 target genes and is required during craniofacial development. Development (Cambridge, England) 18 34414417
2017 Six1 and Eya1 both promote and arrest neuronal differentiation by activating multiple Notch pathway genes. Developmental biology 18 28947179
2017 Characterization of the promoter region of the bovine SIX1 gene: Roles of MyoD, PAX7, CREB and MyoG. Scientific reports 18 28974698
2019 SIX1 Regulates Aberrant Endometrial Epithelial Cell Differentiation and Cancer Latency Following Developmental Estrogenic Chemical Exposure. Molecular cancer research : MCR 17 31597742
2010 Characterization of the Six1 homeobox gene in normal mammary gland morphogenesis. BMC developmental biology 17 20074369

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