Affinage

SIX1

Homeobox protein SIX1 · UniProt Q15475

Length
284 aa
Mass
32.2 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIX1 is a homeodomain transcription factor that orchestrates developmental organogenesis, muscle fiber-type specification, and metabolic reprogramming by binding MEF3-type DNA elements and assembling context-dependent transcriptional complexes. SIX1 forms obligate complexes with EYA family phosphatases, which switch SIX1-DACH repressor complexes to activation mode by recruiting histone acetyltransferases (HBO1, AIB1), directly driving glycolytic gene expression, VEGF-C, TGF-β type I receptor, Fgf8, MyoD, Dusp6, and other targets (PMID:14628042, PMID:29455928, PMID:21056993, PMID:22340499). SIX1 protein stability is tightly controlled by CK2-mediated phosphorylation that abolishes DNA binding, APC/Cdh1-mediated ubiquitin-proteasomal degradation at mitosis, O-GlcNAcylation at T276 that inhibits ubiquitination, and USP1-mediated deubiquitination scaffolded by GRP75 (PMID:10801845, PMID:17130831, PMID:32863962, PMID:34079090). Mutations in SIX1 that disrupt either EYA interaction or DNA binding cause branchio-oto-renal (BOR) syndrome, and SIX1 cooperates with SWI/SNF chromatin remodelers (BRG1, BAF170) and SOX2 to drive neurogenesis and hair cell fate in the inner ear (PMID:15141091, PMID:22513373, PMID:22340499).

Mechanistic history

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

    Establishing that SIX1 is a cell-cycle-regulated phosphoprotein answered how its DNA-binding activity is dynamically controlled: CK2-mediated hyperphosphorylation at mitosis abolishes MEF3 site binding, linking SIX1 transcriptional output to cell cycle state.

    Evidence In vitro CK2 kinase assay, EMSA for MEF3 binding, cell cycle synchronization, CK2 inhibitor treatment

    PMID:10801845

    Open questions at the time
    • Specific CK2 phosphorylation sites on SIX1 not mapped
    • Whether phosphorylation also affects co-factor interactions unknown
    • In vivo physiological consequence of CK2 regulation of SIX1 not tested
  2. 2003 High

    The discovery that EYA proteins possess intrinsic phosphatase activity that switches the SIX1-DACH complex from repression to activation established the core molecular logic of the SIX regulatory network — co-factor enzymatic activity determines transcriptional output.

    Evidence Biochemical phosphatase assays, co-immunoprecipitation, transcriptional reporters, mouse knockouts

    PMID:14628042

    Open questions at the time
    • Identity of the EYA phosphatase substrate(s) in the SIX1-DACH complex not defined
    • Structure of the ternary SIX1-DACH-EYA complex unknown
  3. 2004 High

    Demonstrating that BOR syndrome mutations either abolish SIX1-EYA1 interaction or SIX1-DNA binding — with both classes eliminating transcriptional activation — established that the intact EYA1-SIX1-DNA ternary complex is essential for otic and renal development.

    Evidence Patient mutation sequencing, EMSA, protein-protein interaction assays, luciferase reporters

    PMID:15141091

    Open questions at the time
    • Whether different BOR mutations produce distinct clinical severities through graded biochemical defects not resolved
    • Downstream target genes mediating kidney and ear phenotypes not identified at this stage
  4. 2004 High

    Forced SIX1/EYA1 expression reprogramming slow-twitch to fast-twitch muscle fibers demonstrated that SIX1 specifies glycolytic muscle identity in vivo, extending its role beyond development to adult tissue homeostasis.

    Evidence Transgenic overexpression in soleus muscle, myosin heavy chain isoform analysis, MEF3 promoter reporters

    PMID:15226428

    Open questions at the time
    • Whether endogenous SIX1 is required to maintain fast-twitch identity (loss-of-function) not shown
    • Direct transcriptional targets mediating fiber-type switch not catalogued
  5. 2006 High

    Identification of APC/Cdh1-mediated proteasomal degradation of SIX1 at mitosis revealed a novel non-canonical APC substrate mechanism, explaining how SIX1 protein levels are reset each cell cycle.

    Evidence Proteasome inhibitor treatment, Cdh1 co-immunoprecipitation, deletion mutagenesis, cell cycle staging

    PMID:17130831

    Open questions at the time
    • Exact degron motifs replacing D-box/KEN-box not fully mapped
    • Relationship between CK2 phosphorylation and APC-mediated degradation not tested
  6. 2009 High

    Detailed biochemical analysis of six BOR mutations refined the two-class model and revealed that EYA interaction increases SIX1 protein stability and DNA-binding affinity, establishing EYA as both an enzymatic co-activator and a structural stabilizer of SIX1.

    Evidence Recombinant protein purification, in vitro binding assays, cellular localization, luciferase reporters

    PMID:19497856

    Open questions at the time
    • Structural basis for how EYA binding enhances SIX1 stability not resolved
    • Whether EYA protects SIX1 from specific ubiquitin ligases not tested
  7. 2010 High

    Identifying TGF-β type I receptor as a direct SIX1 transcriptional target that switches TGF-β from tumor-suppressive to pro-metastatic established SIX1 as a master regulator of EMT and metastasis signaling.

    Evidence Knockdown/overexpression in breast cancer lines, TβRI promoter reporters, in vivo metastasis assays

    PMID:21056993

    Open questions at the time
    • Whether SIX1 directly binds TβRI promoter (ChIP) not shown at this stage
    • Mechanism of signaling switch from tumor suppression to promotion not fully delineated
  8. 2011 High

    Three studies collectively placed SIX1 within defined developmental signaling cascades: SIX1/EYA1 directly activates Fgf8 downstream of Tbx1 in cardiovascular/craniofacial development, regulates Grem1 to antagonize BMP4 in kidney branching morphogenesis, and requires EYA2 for pro-metastatic TGF-β/EMT functions in cancer.

    Evidence Genetic epistasis in compound mutant mice, recombinant GREM1 rescue of Six1-null kidneys, EYA2 knockdown epistasis in breast cancer cells

    PMID:21281623 PMID:21364285 PMID:21706047

    Open questions at the time
    • Whether SIX1 directly binds Grem1 regulatory elements not confirmed by ChIP
    • How SIX1/EYA1 vs SIX1/EYA2 co-factor choice is determined in different tissues unknown
  9. 2012 High

    A series of 2012 studies expanded SIX1's mechanisms in four directions: (1) SIX1/EYA1 recruit SWI/SNF (BRG1/BAF170) for neurogenesis, (2) SIX1/EYA1/SOX2 drive hair cell fate via Atoh1 enhancers, (3) SIX1 transcriptionally induces VEGF-C for lymphangiogenesis, (4) SIX1 directly activates Dusp6 to regulate satellite cell ERK signaling, and (5) SIX1's DNA-binding specificity extends beyond the homeodomain.

    Evidence Co-IP with BRG1/BAF170, BRG1 ATPase-dead mutant, Atoh1 enhancer mutagenesis, cochlear explants, VEGF-C promoter reporters plus xenograft lymphangiogenesis, Dusp6 ChIP in satellite cells, ChIP-seq binding profile optimization

    PMID:22340499 PMID:22466647 PMID:22513373 PMID:22730291 PMID:22945933

    Open questions at the time
    • Whether SWI/SNF is recruited genome-wide or at specific SIX1 targets not determined
    • Relative contribution of VEGF-C-dependent vs independent SIX1 metastasis pathways unquantified
    • Structural basis of SIX1 DNA-binding site selection by non-homeodomain regions unknown
  10. 2013 High

    SIX1 was shown to directly bind the MyoD core enhancer to maintain chromatin accessibility and MyoD expression, and to activate cyclin D1 transcription for cell cycle progression, broadening the direct target gene repertoire.

    Evidence ChIP at MyoD enhancer in myoblasts, siRNA knockdown, cyclin D1 promoter-reporter assays in pancreatic cancer cells

    PMID:23527134 PMID:23840772

    Open questions at the time
    • Cyclin D1 activation lacks ChIP confirmation of direct binding
    • Whether SIX1's role at MyoD enhancer requires EYA co-factors not tested
  11. 2015 High

    Discovery that SIX1 downregulates p53 through a miR-27a-3p/RPL26 dual mechanism, independent of MDM2, revealed a non-canonical route by which SIX1 suppresses tumor surveillance.

    Evidence miRNA overexpression/knockdown, RPL26 mutation analysis, western blot for p53 pathway components

    PMID:26687066

    Open questions at the time
    • Whether SIX1 directly transcribes miR-27a-3p or acts indirectly not established
    • Physiological relevance during normal development unknown
  12. 2016 High

    Genome-wide analysis demonstrated that SIX1/Six4 MEF3 binding sites co-localize with MyoD sites at >1000 genomic loci, establishing a feedforward transcriptional network for myogenic reprogramming, and Pa2G4 was identified as a novel SIX1-binding co-factor that competes with EYA1.

    Evidence MyoD ChIP-seq with MEF3 motif mapping in reprogrammed MEFs, Pa2G4 co-IP in HEK cells, Xenopus knockdown

    PMID:27302134 PMID:27940157

    Open questions at the time
    • Pa2G4-SIX1 interaction confirmed only by single co-IP direction
    • Whether Pa2G4 modulates SIX1 targets genome-wide not tested
  13. 2017 Medium

    SIX1 was found to regulate dorsal mandibular arch identity by inducing Jag1 and repressing Edn1, with loss causing aberrant EDNRA signaling and partial mandibular duplication — revealing a role in craniofacial patterning distinct from inner ear development.

    Evidence Conditional Six1 knockout, in situ hybridization, genetic epistasis with EDNRA pathway

    PMID:28455376

    Open questions at the time
    • Whether SIX1 directly binds Jag1 and Edn1 regulatory regions not shown
    • Mechanism of SIX1-mediated repression of Edn1 unknown
  14. 2018 High

    ChIP-seq revealed that SIX1 directly occupies promoters of glycolytic genes and recruits HBO1/AIB1 histone acetyltransferases to drive aerobic glycolysis (Warburg effect), providing the mechanistic basis for SIX1's metabolic reprogramming function in cancer.

    Evidence ChIP-seq, HAT inhibitor studies, metabolic flux assays, cancer-associated SIX1 mutant analysis, in vivo tumor growth

    PMID:29455928

    Open questions at the time
    • Whether HBO1/AIB1 recruitment is EYA-dependent or independent not fully resolved
    • Structural basis of SIX1-HAT interaction unknown
  15. 2020 High

    Two advances in 2020 addressed SIX1 protein stability and pharmacological targeting: O-GlcNAcylation at T276 was shown to inhibit ubiquitin-mediated degradation, and a small molecule disrupting SIX1-EYA2 interaction reversed EMT, TGF-β signaling, and metastasis in vivo.

    Evidence Mass spectrometry for O-GlcNAc site, T276A mutagenesis with ubiquitination assays; small-molecule screen with co-IP assessment, transcriptome profiling, in vivo metastasis model

    PMID:32341035 PMID:32863962

    Open questions at the time
    • O-GlcNAc transferase responsible for T276 modification not identified
    • Small molecule's direct binding mode and selectivity not structurally characterized
    • Relationship between O-GlcNAcylation and APC/Cdh1-mediated degradation not tested
  16. 2021 High

    Identification of a GRP75-USP1-SIX1 trimeric complex revealed the deubiquitination mechanism that stabilizes SIX1: GRP75 scaffolds USP1 to remove K48-linked polyubiquitin chains from SIX1, directly opposing proteasomal degradation.

    Evidence Co-immunoprecipitation, domain mapping of GRP75 C-terminus, K48-ubiquitination assays, xenograft models

    PMID:34079090

    Open questions at the time
    • Whether USP1-mediated stabilization operates during normal development or only in cancer contexts unknown
    • Specific lysine residues on SIX1 targeted by USP1 not mapped
  17. 2022 Medium

    Placing USP1-mediated SIX1 stabilization downstream of EGFR-AKT signaling revealed how growth factor signaling sustains SIX1 protein levels in hepatocellular carcinoma.

    Evidence USP1 knockdown/overexpression, EGFR inhibitor treatment, ubiquitination assays, xenograft models

    PMID:36261513

    Open questions at the time
    • Whether AKT directly phosphorylates USP1 to regulate its activity not determined
    • Generalizability beyond hepatocellular carcinoma not tested
  18. 2023 Medium

    SIX1 was shown to directly bind the LDHA promoter and activate transcription, linking SIX1-driven lactate production to immune evasion via NK cell dysfunction in the tumor microenvironment.

    Evidence ChIP at LDHA promoter, metabolic assays, NK cell co-culture, LDHA inhibitor rescue, xenograft models

    PMID:36937004

    Open questions at the time
    • Whether LDHA is activated through HBO1/AIB1 co-activators as for other glycolytic targets not tested
    • In vivo immune phenotype confirmation in immunocompetent models lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis of SIX1-EYA and SIX1-DACH complex assembly, how tissue-specific co-factor choice (EYA1 vs EYA2 vs Pa2G4) is determined, the identity of the E3 ubiquitin ligase(s) opposing USP1 at steady state, and whether the diverse post-translational regulatory mechanisms (CK2 phosphorylation, O-GlcNAcylation, APC/Cdh1 degradation, USP1 deubiquitination) are integrated or operate in distinct cellular contexts.
  • No crystal or cryo-EM structure of any SIX1-containing complex
  • Tissue-specific co-factor selectivity mechanism unknown
  • Identity of the E3 ligase(s) that ubiquitinate SIX1 outside of APC/Cdh1 not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 2 R-HSA-4839726 Chromatin organization 2
Partners
BRG1DACH1EYA1EYA2GRP75PA2G4SOX2USP1
Complex memberships
GRP75-USP1-SIX1SIX1-EYA1-BRG1-BAF170 (SWI/SNF)SIX1-EYA1/EYA2-DACH

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 SIX1 forms a transcriptional complex with DACH and EYA proteins; EYA family members possess protein phosphatase activity, and this enzymatic activity switches the SIX1-DACH complex from transcriptional repression to activation by recruiting co-activators to specific gene targets regulating precursor cell proliferation. Biochemical phosphatase assays, co-immunoprecipitation, transcriptional reporter assays, genetic mouse knockouts Nature High 14628042
2004 BOR syndrome-causing SIX1 mutations disrupt either EYA1-SIX1 protein-protein interaction or SIX1-DNA binding; all three identified mutations abolish transcriptional activation, establishing that the EYA1-SIX1-DNA complex is required for normal otic and renal development. Direct sequencing, protein-protein interaction assays, DNA binding assays (EMSA), transcriptional reporter assays PNAS High 15141091
2000 SIX1 is a nuclear phosphoprotein that undergoes hyperphosphorylation at mitosis by casein kinase II (CK2); CK2-mediated phosphorylation abolishes SIX1 binding to MEF3 sites in the aldolase A promoter, and CK2 inhibition arrests cells at G2/M. Cell cycle synchronization, in vitro kinase assay with CK2, EMSA for DNA binding, CK2 inhibitor (apigenin) treatment, immunoprecipitation Journal of Biological Chemistry High 10801845
2004 SIX1 and EYA1 together reprogram adult slow-twitch oxidative muscle fibers toward a fast-twitch glycolytic phenotype; SIX1 and EYA1 proteins preferentially accumulate in nuclei of fast-twitch muscles, and the MEF3/Six DNA binding element in the aldolase A pM promoter mediates high-level activation specifically in fast-twitch fibers. Transgenic forced expression in soleus muscle, myosin heavy chain isoform analysis, promoter-reporter assays, immunolocalization Molecular and Cellular Biology High 15226428
2006 SIX1 protein is degraded via ubiquitin-mediated proteolysis through the APC(Cdh1) complex at mitosis; unlike canonical APC targets, SIX1 lacks destruction or KEN box motifs, instead containing multiple N- and C-terminal sequences including an N-terminal region that binds Cdh1. Cell cycle synchronization, proteasome inhibitor assays, co-immunoprecipitation with Cdh1, deletion mutagenesis Oncogene High 17130831
2009 SIX1 BOR syndrome mutations act through two distinct mechanisms: the V17E mutation in the Six domain abolishes SIX1-EYA complex formation and prevents nuclear localization of EYA, while the remaining five mutations retain EYA binding but are deficient in DNA binding; all mutants fail transcriptional activation. EYA interaction increases SIX1 protein stability and DNA binding affinity. Recombinant protein expression/purification in E. coli, in vitro binding assays, cellular localization studies, luciferase reporter assays Journal of Biological Chemistry High 19497856
2010 SIX1 promotes epithelial-mesenchymal transition (EMT) and metastasis through upregulation of TGF-β type I receptor (TβRI), which is both necessary and sufficient to activate TGF-β signaling and induce EMT properties; SIX1 overexpression is required to switch TGF-β from tumor-suppressive to pro-metastatic. Knockdown/overexpression in breast cancer cell lines, TβRI promoter-reporter assays, in vivo metastasis assays Cancer Research High 21056993
2011 EYA2 is a required co-factor for SIX1 to mediate pro-metastatic functions including induction of TGF-β signaling, EMT, and cancer stem cell properties in breast cancer cells; knockdown of EYA2 reverses SIX1-induced phenotypes. siRNA knockdown, EMT marker analysis, TGF-β pathway reporter assays, cancer stem cell assays in MCF7 cells Oncogene High 21706047
2012 EYA1 and SIX1 interact directly with SWI/SNF chromatin-remodeling subunits BRG1 and BAF170 to drive neurogenesis; the ATPase activity of BRG1 is required for EYA1/SIX1-induced ectopic neurogenesis and normal neurogenesis in the otocyst. SOX2 cooperates with EYA1/SIX1 in this complex to mediate neuronal differentiation upstream of NEUROG1 and NEUROD1. Co-immunoprecipitation, overexpression in non-neuronal cells (3T3 fibroblasts), cochlear explants, otocyst gain-of-function, BRG1 ATPase-dead mutant Development High 22513373
2012 EYA1/SIX1 coexpression in mouse cochlear explants is sufficient to induce hair cell fate in non-sensory epithelium by activating Atoh1-dependent and Atoh1-independent pathways; SOX2 cooperates with EYA1/SIX1 by direct binding to conserved Sox- and Six-binding sites in Atoh1 enhancers, and these proteins physically interact. Cochlear explant overexpression, Atoh1 enhancer reporter assays with site-directed mutagenesis, co-immunoprecipitation, conditional knockout mice Developmental Cell High 22340499
2012 SIX1 transcriptionally induces VEGF-C expression, promoting peritumoral and intratumoral lymphangiogenesis and lymphatic metastasis in breast cancer; VEGF-C induction is required for SIX1-mediated lymphangiogenesis but additional VEGF-C-independent pathways also contribute to metastasis. Xenograft models in immunocompromised mice, VEGF-C promoter-reporter assays, siRNA knockdown, in vivo lymphangiogenesis quantification Journal of Clinical Investigation High 22466647
2012 SIX1 regulates skeletal muscle satellite cell differentiation and self-renewal via the ERK1/2 pathway through direct transcriptional control of Dusp6, a phosphatase that modulates ERK1/2 activity; genetic disruption of Six1 specifically in adult satellite cells impairs myofiber repair and increases stem cell self-renewal. Conditional Six1 knockout in adult satellite cells, chromatin immunoprecipitation (ChIP) for Dusp6, regeneration assays, Dusp6-null mice analysis Journal of Cell Biology High 22945933
2013 SIX1 directly binds to the Core Enhancer Region of MyoD in muscle progenitor cells, is required for proper chromatin structure at this enhancer, and promotes MyoD binding at its own enhancer; Six1 knockdown reduces MyoD expression in myoblasts. Chromatin immunoprecipitation (ChIP), transcriptional reporter assays, siRNA knockdown, regenerating muscle analysis PLoS One High 23840772
2013 SIX1 directly transcriptionally activates cyclin D1, promoting cell cycle progression and proliferation; SIX1 overexpression upregulates cyclin D1 mRNA and protein and enhances cyclin D1 promoter activity in pancreatic cancer cells. Cyclin D1 promoter-luciferase reporter assays, qRT-PCR, western blot, xenograft assays PLoS One Medium 23527134
2014 SIX1 coordinates TGF-β signals to upregulate VEGF-C expression in cervical cancer cells; SIX1 enhances TGF-β-induced SMAD2/3 activation and cooperates with the SMAD pathway to promote VEGF-C expression and lymphangiogenesis. SMAD2/3 phosphorylation analysis, VEGF-C promoter assays, in vitro lymphangiogenesis assays, knockdown/overexpression in tumor cells Cancer Research Medium 25142796
2015 SIX1 decreases p53 levels through a dual mechanism: (1) upregulation of microRNA-27a-3p that targets p53, and (2) downregulation of RPL26, which normally inhibits miR-27a-mediated repression of p53; these mechanisms operate independently of MDM2. Transcriptional reporter assays, miRNA overexpression/knockdown, RPL26 mutation analysis, western blot for p53 pathway components Nature Communications High 26687066
2018 SIX1 directly increases expression of many glycolytic genes to promote the Warburg effect; this transcriptional regulation of glycolysis occurs through HBO1 and AIB1 histone acetyltransferases; a cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis. ChIP-seq for SIX1 binding at glycolytic gene promoters, HAT inhibitor studies, SIX1 mutant overexpression, metabolic flux assays, in vivo tumor growth Cancer Cell High 29455928
2020 O-GlcNAcylation of SIX1 at threonine 276 (T276) enhances its stability by inhibiting ubiquitin-mediated proteasomal degradation; SIX1 itself promotes O-GlcNAcylation levels, forming a feedback loop; T276A mutation reduces O-GlcNAcylation and reverses the pro-tumor effect. Mass spectrometry, immunoprecipitation, site-directed mutagenesis (T276A), ubiquitination assays, xenograft models Theranostics High 32863962
2021 GRP75 forms a trimeric complex with USP1 (a deubiquitinating enzyme) and SIX1; GRP75 provides a scaffold to recruit USP1, which inhibits K48-linked polyubiquitination of SIX1, thereby stabilizing SIX1 protein in prostate cancer cells; the C-terminus of GRP75 (433-679 aa) containing a peptide binding domain is required for complex formation. Co-immunoprecipitation, domain mapping, K48-ubiquitination assays, genetic and pharmacological inhibition, xenograft mouse models Oncogene High 34079090
2022 USP1 deubiquitinase stabilizes SIX1 protein in hepatocellular carcinoma through the EGFR-AKT signaling axis; EGFR-AKT activation promotes USP1 expression, which in turn prevents SIX1 degradation; suppression of this axis with SNS-032 induces SIX1 degradation. Ubiquitination assays, USP1 knockdown/overexpression, EGFR inhibitor experiments, western blot, xenograft models Acta Pharmacologica Sinica Medium 36261513
2020 A small molecule (NCGC00378430/8430) that reduces the SIX1/EYA2 protein-protein interaction partially reverses SIX1-induced transcriptional and metabolic profiles, reverses TGF-β signaling and EMT, and suppresses breast cancer metastasis in vivo without affecting primary tumor growth. Small molecule screen, co-immunoprecipitation to assess complex disruption, transcriptome profiling, metabolic assays, in vivo metastasis model Cancer Research High 32341035
2011 SIX1 and EYA1 form a transcription complex that directly regulates Fgf8 expression, acting downstream of Tbx1 in a genetic pathway (Tbx1-Six1/Eya1-Fgf8) controlling cardiovascular and craniofacial development; Six1/Eya1 double mutant mice recapitulate human del22q11 syndrome features. Genetic epistasis in mouse double mutants, Fgf8 promoter assays, compound mutant rescue experiments Journal of Clinical Investigation High 21364285
2011 SIX1 acts in the metanephric mesenchyme as an upstream regulator of Grem1 expression; loss of Six1 abolishes Grem1 expression, leading to unopposed BMP4 activity that prevents ureteric bud ampulla formation; GREM1 protein treatment or genetic reduction of BMP4 restores branching morphogenesis in Six1-null kidneys. Six1 knockout mouse analysis, recombinant GREM1 treatment of kidney rudiments, genetic rescue (Six1−/−; Bmp4+/−), in vitro kidney culture Developmental Biology High 21281623
2016 Six1 and Six4 are both required for MyoD reprogramming of mouse embryonic fibroblasts toward myogenic fate; Six1/Six4 binding sites (MEF3 motifs) co-localize with MyoD binding sites on over 1000 genomic regions; Six1 and MyoD act synergistically in a feedforward transcriptional network to activate >80 co-regulated genes. MyoD-driven reprogramming of MEFs with Six1/Six4 knockdown, microarray gene expression, MyoD ChIP-seq analysis, genome-wide MEF3 site mapping, luciferase reporter assays Nucleic Acids Research High 27302134
2012 Six1 optimal DNA-binding sequence is broader than previously known; Six1 domains outside the homeodomain contribute to DNA binding site selection, and Six1 alone (without co-factors) is sufficient for sequence discrimination at MEF3-type sites. Genomic ChIP binding profile analysis in myoblasts, position weight matrix optimization, in vitro DNA binding assays Nucleic Acids Research Medium 22730291
2016 Pa2G4 (Ebp1/Plfap) is a novel SIX1 co-factor that binds to SIX1 and interferes with the SIX1-EYA1 complex in human embryonic kidney cells; in Xenopus, Pa2G4 knockdown reduces neural crest and placodal gene expression and affects otocyst development. Co-immunoprecipitation in HEK cells, Xenopus gain- and loss-of-function, otocyst marker analysis Developmental Biology Medium 27940157
2018 SIX1 expression in leukemic initiating cells is controlled by WNT/β-catenin signaling through TCF7L2; the oncofusion protein MLL-AF9 increases chromatin accessibility at TCF/LEF-binding elements controlling the Six1 locus, enabling TCF7L2-dependent transcriptional activation of Six1. ATAC-seq, transcriptome profiling, WNT inhibitor treatment, genetic deletion of Wntless (WLS) in mice, AML mouse model EBioMedicine Medium 30528456
2023 SIX1 directly binds the LDHA promoter region to transcriptionally activate LDHA expression, promoting lactate accumulation in pancreatic cancer cells; SIX1-driven lactate production leads to NK cell dysfunction in the tumor microenvironment. Chromatin immunoprecipitation (ChIP) for SIX1 at LDHA promoter, metabolic assays, NK cell co-culture assays, xenograft models, LDHA inhibitor rescue experiments Journal of Immunology Research Medium 36937004
2017 SIX1 regulates dorsal mandibular arch identity by inducing Jag1 expression and simultaneously inhibiting Edn1 (endothelin 1) expression in pharyngeal endoderm; loss of SIX1 leads to aberrant EDNRA signaling in the dorsal arch domain, resulting in partial mandibular duplication. Six1 conditional knockout mice, Edn1/Jag1 expression analysis by in situ hybridization, genetic epistasis with EDNRA pathway mutants Development Medium 28455376

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 534 14628042
2018 Transcriptional Regulation of the Warburg Effect in Cancer by SIX1. Cancer cell 325 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 305 15141091
2003 The role of Six1 in mammalian auditory system development. Development (Cambridge, England) 290 12874121
2015 Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors. Cancer cell 242 25670083
2003 Altered myogenesis in Six1-deficient mice. Development (Cambridge, England) 214 12668636
2004 Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes. Development (Cambridge, England) 195 15496442
2012 Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. Developmental cell 193 22340499
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
2009 Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition. The Journal of clinical investigation 147 19726883
2005 Tissues and signals involved in the induction of placodal Six1 expression in Xenopus laevis. Developmental biology 133 16271713
2011 Eya2 is required to mediate the pro-metastatic functions of Six1 via the induction of TGF-β signaling, epithelial-mesenchymal transition, and cancer stem cell properties. Oncogene 118 21706047
2011 A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis. The Journal of clinical investigation 112 21364285
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) 109 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 105 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 88 18571637
2012 Six1 regulates stem cell repair potential and self-renewal during skeletal muscle regeneration. The Journal of cell biology 87 22945933
2013 Six1 promotes proliferation of pancreatic cancer cells via upregulation of cyclin D1 expression. PloS one 84 23527134
2006 Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma. British journal of cancer 84 17008870
2014 SIX1 promotes tumor lymphangiogenesis by coordinating TGFβ signals that increase expression of VEGF-C. Cancer research 81 25142796
2008 Initiation of olfactory placode development and neurogenesis is blocked in mice lacking both Six1 and Six4. Developmental biology 79 19027001
2011 Mutation screening of the EYA1, SIX1, and SIX5 genes in a large cohort of patients harboring branchio-oto-renal syndrome calls into question the pathogenic role of SIX5 mutations. Human mutation 78 21280147
2013 Homeoproteins Six1 and Six4 regulate male sex determination and mouse gonadal development. Developmental cell 77 23987514
2006 The transcription factor six1 inhibits neuronal and promotes hair cell fate in the developing zebrafish (Danio rerio) inner ear. The Journal of neuroscience : the official journal of the Society for Neuroscience 74 17035528
2008 SIX1 mutation screening in 247 branchio-oto-renal syndrome families: a recurrent missense mutation associated with BOR. Human mutation 71 18330911
2008 Expression of effector gene SIX1 of Fusarium oxysporum requires living plant cells. Fungal genetics and biology : FG & B 68 18606236
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
2017 Six1 promotes colorectal cancer growth and metastasis by stimulating angiogenesis and recruiting tumor-associated macrophages. Carcinogenesis 66 28199476
2014 miR-30b regulates migration and invasion of human colorectal cancer via SIX1. The Biochemical journal 61 24593661
2014 miR-204 functions as a tumor suppressor by regulating SIX1 in NSCLC. FEBS letters 60 25157435
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
2018 MiR-448-5p inhibits TGF-β1-induced epithelial-mesenchymal transition and pulmonary fibrosis by targeting Six1 in asthma. Journal of cellular physiology 52 30362537
2015 The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. Nature communications 49 26687066
2019 MiR-150-5p regulates melanoma proliferation, invasion and metastasis via SIX1-mediated Warburg Effect. Biochemical and biophysical research communications 43 31128917
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
2020 Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis. Cancer research 41 32341035
2019 miR-186-5p targeting SIX1 inhibits cisplatin resistance in non-small-cell lung cancer cells (NSCLCs). Neoplasma 41 31686523
2018 miR-204-5p suppresses hepatocellular cancer proliferation by regulating homeoprotein SIX1 expression. FEBS open bio 41 29435409
2012 Regulation of Six1 expression by evolutionarily conserved enhancers in tetrapods. Developmental biology 40 22659139
2020 Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4. Gut 39 32826305
2019 Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development. Journal of dental research 39 30905259
2017 Negative regulation of endothelin signaling by SIX1 is required for proper maxillary development. Development (Cambridge, England) 39 28455376
2011 Six1 transcription factor is critical for coordination of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung. Developmental biology 39 21385574
2020 MicroRNA-155-3p promotes glioma progression and temozolomide resistance by targeting Six1. Journal of cellular and molecular medicine 38 32220051
2014 HDAC5 promotes cell proliferation in human hepatocellular carcinoma by up-regulating Six1 expression. European review for medical and pharmacological sciences 38 24706304
2020 The Marine Natural Product Manzamine A Inhibits Cervical Cancer by Targeting the SIX1 Protein. Journal of natural products 37 32022559
2019 miR-140-5p induces cell apoptosis and decreases Warburg effect in chronic myeloid leukemia by targeting SIX1. Bioscience reports 37 30962263
2014 The role of Six1 in the genesis of muscle cell and skeletal muscle development. International journal of biological sciences 37 25210496
2009 Biochemical and functional characterization of six SIX1 Branchio-oto-renal syndrome mutations. The Journal of biological chemistry 37 19497856
2019 lncRNA FOXD2-AS1 confers cisplatin resistance of non-small-cell lung cancer via regulation of miR185-5p-SIX1 axis. OncoTargets and therapy 36 31534348
2017 microRNA-488 inhibits chemoresistance of ovarian cancer cells by targeting Six1 and mitochondrial function. Oncotarget 36 29113360
2013 Six1 regulates MyoD expression in adult muscle progenitor cells. PloS one 36 23840772
2010 Canonical Wnt signaling modulates Tbx1, Eya1, and Six1 expression, restricting neurogenesis in the otic vesicle. Developmental dynamics : an official publication of the American Association of Anatomists 36 20503367
2022 Ginsenoside Rh4 Suppresses Metastasis of Gastric Cancer via SIX1-Dependent TGF-β/Smad2/3 Signaling Pathway. Nutrients 35 35458126
2016 The role of Six1 signaling in paclitaxel-dependent apoptosis in MCF-7 cell line. Bosnian journal of basic medical sciences 35 26773176
2006 Cell cycle regulation of the human Six1 homeoprotein is mediated by APC(Cdh1). Oncogene 35 17130831
2016 SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer. Molecular cancer research : MCR 34 27259717
2014 Six1 promotes epithelial-mesenchymal transition and malignant conversion in human papillomavirus type 16-immortalized human keratinocytes. Carcinogenesis 34 24574515
2013 Mutational analysis of EYA1, SIX1 and SIX5 genes and strategies for management of hearing loss in patients with BOR/BO syndrome. PloS one 34 23840632
2013 Combinatorial activity of Six1-2-4 genes in cephalic neural crest cells controls craniofacial and brain development. Cellular and molecular life sciences : CMLS 34 24061537
2021 A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance. Oncogene 33 34079090
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
2017 Six1 is essential for differentiation and patterning of the mammalian auditory sensory epithelium. PLoS genetics 32 28892484
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
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
2011 Six1 regulates Grem1 expression in the metanephric mesenchyme to initiate branching morphogenesis. Developmental biology 28 21281623
2023 The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer. Journal of immunology research 27 36937004
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
2012 EYA1-SIX1 complex in neurosensory cell fate induction in the mammalian inner ear. Hearing research 26 23104013
2018 Transcriptional Regulation by CpG Sites Methylation in the Core Promoter Region of the Bovine SIX1 Gene: Roles of Histone H4 and E2F2. International journal of molecular sciences 25 29337851
2016 Chromosomal anomalies at 1q, 3, 16q, and mutations of SIX1 and DROSHA genes underlie Wilms tumor recurrences. Oncotarget 25 26802027
2016 MyoD reprogramming requires Six1 and Six4 homeoproteins: genome-wide cis-regulatory module analysis. Nucleic acids research 25 27302134
2020 MiR-203a-3p regulates TGF-β1-induced epithelial-mesenchymal transition (EMT) in asthma by regulating Smad3 pathway through SIX1. Bioscience reports 24 32065213
2022 SNS-023 sensitizes hepatocellular carcinoma to sorafenib by inducing degradation of cancer drivers SIX1 and RPS16. Acta pharmacologica Sinica 23 36261513
2016 Pa2G4 is a novel Six1 co-factor that is required for neural crest and otic development. Developmental biology 23 27940157
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
2014 MicroRNA-30a regulates zebrafish myogenesis through targeting the transcription factor Six1. Journal of cell science 22 24634509
2013 Abrogation of Eya1/Six1 disrupts the saccular phase of lung morphogenesis and causes remodeling. Developmental biology 22 23895934
2023 SIX1 amplification modulates stemness and tumorigenesis in breast cancer. Journal of translational medicine 21 38031089
2022 Tanshinone IIA inhibits cell growth by suppressing SIX1-induced aerobic glycolysis in non-small cell lung cancer cells. Oncology letters 21 35527783
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
2018 Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9. EBioMedicine 21 30528456
2015 Six1 promotes glioblastoma cell proliferation and invasion by upregulation of connective tissue growth factor. American journal of cancer research 21 26175950
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