SIX4 SIX homeobox 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: SIX4provided by HGNC
Official Full Name: SIX homeobox 4provided by HGNC
Primary source: HGNC:HGNC:10890
See related: Ensembl:ENSG00000100625 MIM:606342; AllianceGenome:HGNC:10890
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: AREC3
Summary: This gene encodes a member of the homeobox family, subfamily SIX. The drosophila homolog is a nuclear homeoprotein required for eye development. Studies in mouse show that this gene product functions as a transcription factor, and may have a role in the differentiation or maturation of neuronal cells. [provided by RefSeq, May 2010]
Expression: Broad expression in prostate (RPKM 2.0), salivary gland (RPKM 1.8) and 16 other tissues See more
Orthologs: all
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Genomic context

Location:: 14q23.1

Exon count:: 5

Annotation release	Status	Assembly	Chr	Location
RS_2025_08	current	GRCh38.p14 (GCF_000001405.40)	14	NC_000014.9 (60709539..60724351, complement)
RS_2025_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	14	NC_060938.1 (54916015..54930882, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	14	NC_000014.8 (61176257..61191069, complement)

Chromosome 14 - NC_000014.9 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: Tissue-specific circular RNA induction during human fetal development
Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
BioProject: PRJNA270632
Publication: PMID 26076956
Analysis date: Mon Apr 2 22:54:59 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Knockdown of SIX4 inhibits pancreatic cancer cells via apoptosis induction.
Title: Knockdown of SIX4 inhibits pancreatic cancer cells via apoptosis induction.
SIX4 upregulates IDH1 and metabolic reprogramming to promote osteosarcoma progression.
Title: SIX4 upregulates IDH1 and metabolic reprogramming to promote osteosarcoma progression.
IGF2BP3stabilized SIX4 promotes the proliferation, migration, invasion and tube formation of ovarian cancer cells.
Title: IGF2BP3‑stabilized SIX4 promotes the proliferation, migration, invasion and tube formation of ovarian cancer cells.
Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4alpha and SIX1/4.
Title: Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4.
Upregulation of SIX4 indicates poor clinical outcome and promotes tumor growth and cell metastasis in esophageal squamous cell carcinoma.
Title: Upregulation of SIX4 indicates poor clinical outcome and promotes tumor growth and cell metastasis in esophageal squamous cell carcinoma.
SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET.
Title: SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET.
Circular RNA-hsa-circ-0000670 promotes gastric cancer progression through the microRNA-384/SIX4 axis.
Title: Circular RNA-hsa-circ-0000670 promotes gastric cancer progression through the microRNA-384/SIX4 axis.
MiRNA-621 inhibits the malignant progression of non-small cell lung cancer via targeting SIX4.
Title: MiRNA-621 inhibits the malignant progression of non-small cell lung cancer via targeting SIX4.
SIX4 acts as a master regulator of oncogenes that promotes tumorigenesis in non-small-cell lung cancer cells.
Title: SIX4 acts as a master regulator of oncogenes that promotes tumorigenesis in non-small-cell lung cancer cells.
High SIX4 expression is associated with colorectal cancer angiogenesis.
Title: SIX4 activates Akt and promotes tumor angiogenesis.

Submit: New GeneRIF Correction See all GeneRIFs (11)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Copy number response

Description
Copy number response Haploinsufficency No evidence available (Last evaluated 2012-05-08) ClinGen Genome Curation Page Triplosensitivity No evidence available (Last evaluated 2012-05-08) ClinGen Genome Curation Page

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

D11S2921 (e-PCR)
- UniSTS:152074

D8S2278 (e-PCR)
- UniSTS:473906

D8S2279 (e-PCR)
- UniSTS:473907

L18426 (e-PCR)
- UniSTS:34648

D1S1423 (e-PCR)
- UniSTS:149619

RH103360 (e-PCR)
- UniSTS:97690

RH93867 (e-PCR)
- UniSTS:84980

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables DNA binding	IEA Inferred from Electronic Annotation more info
enables DNA-binding transcription activator activity, RNA polymerase II-specific	IEA Inferred from Electronic Annotation more info
enables DNA-binding transcription factor activity	IEA Inferred from Electronic Annotation more info
enables DNA-binding transcription factor activity, RNA polymerase II-specific	IBA Inferred from Biological aspect of Ancestor more info
enables DNA-binding transcription factor activity, RNA polymerase II-specific	IEA Inferred from Electronic Annotation more info
enables DNA-binding transcription factor activity, RNA polymerase II-specific	ISA Inferred from Sequence Alignment more info
enables RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA Inferred from Biological aspect of Ancestor more info
enables RNA polymerase II cis-regulatory region sequence-specific DNA binding	IEA Inferred from Electronic Annotation more info
enables sequence-specific DNA binding	IEA Inferred from Electronic Annotation more info
enables sequence-specific double-stranded DNA binding	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
involved_in anatomical structure morphogenesis	TAS Traceable Author Statement more info	PubMed
involved_in fungiform papilla morphogenesis	IEA Inferred from Electronic Annotation more info
involved_in fungiform papilla morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in generation of neurons	IEA Inferred from Electronic Annotation more info
involved_in generation of neurons	ISS Inferred from Sequence or Structural Similarity more info
involved_in male gonad development	IEA Inferred from Electronic Annotation more info
involved_in male gonad development	ISS Inferred from Sequence or Structural Similarity more info
involved_in male sex determination	IEA Inferred from Electronic Annotation more info
involved_in male sex determination	ISS Inferred from Sequence or Structural Similarity more info
involved_in male sex differentiation	IEA Inferred from Electronic Annotation more info
involved_in male sex differentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in metanephric mesenchyme development	IEA Inferred from Electronic Annotation more info
involved_in metanephric mesenchyme development	ISS Inferred from Sequence or Structural Similarity more info
involved_in myotome development	IEA Inferred from Electronic Annotation more info
involved_in myotome development	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of DNA-templated transcription	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of DNA-templated transcription	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of apoptotic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of neuron apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of neuron apoptotic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of satellite cell differentiation	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of satellite cell differentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in olfactory placode formation	IEA Inferred from Electronic Annotation more info
involved_in olfactory placode formation	ISS Inferred from Sequence or Structural Similarity more info
involved_in pharyngeal system development	IEA Inferred from Electronic Annotation more info
involved_in pharyngeal system development	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of DNA-templated transcription	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of branching involved in ureteric bud morphogenesis	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of branching involved in ureteric bud morphogenesis	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of transcription by RNA polymerase II	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of ureteric bud formation	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of ureteric bud formation	ISS Inferred from Sequence or Structural Similarity more info
involved_in protein localization to nucleus	IEA Inferred from Electronic Annotation more info
involved_in protein localization to nucleus	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of DNA-templated transcription	IEA Inferred from Electronic Annotation more info
involved_in regulation of branch elongation involved in ureteric bud branching	IEA Inferred from Electronic Annotation more info
involved_in regulation of branch elongation involved in ureteric bud branching	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of epithelial cell proliferation	IEA Inferred from Electronic Annotation more info
involved_in regulation of epithelial cell proliferation	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of transcription by RNA polymerase II	IBA Inferred from Biological aspect of Ancestor more info
involved_in sarcomere organization	IEA Inferred from Electronic Annotation more info
involved_in sarcomere organization	ISS Inferred from Sequence or Structural Similarity more info
involved_in skeletal muscle fiber differentiation	IEA Inferred from Electronic Annotation more info
involved_in skeletal muscle fiber differentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in skeletal muscle tissue development	IEA Inferred from Electronic Annotation more info
involved_in skeletal muscle tissue development	ISS Inferred from Sequence or Structural Similarity more info
involved_in tongue development	IEA Inferred from Electronic Annotation more info
involved_in tongue development	ISS Inferred from Sequence or Structural Similarity more info
involved_in trigeminal ganglion development	IEA Inferred from Electronic Annotation more info
involved_in trigeminal ganglion development	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
located_in chromatin	ISA Inferred from Sequence Alignment more info
located_in cytoplasm	IEA Inferred from Electronic Annotation more info
located_in cytoplasm	ISS Inferred from Sequence or Structural Similarity more info
is_active_in nucleus	IBA Inferred from Biological aspect of Ancestor more info
located_in nucleus	IEA Inferred from Electronic Annotation more info
located_in nucleus	ISS Inferred from Sequence or Structural Similarity more info
part_of transcription regulator complex	IBA Inferred from Biological aspect of Ancestor more info

General protein information

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Preferred Names: homeobox protein SIX4

Names: sine oculis homeobox homolog 4

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_021182.1 RefSeqGene

Range

4784..19596

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_017420.5 → NP_059116.3 homeobox protein SIX4

See identical proteins and their annotated locations for NP_059116.3

Status: REVIEWED

Source sequence(s)

AA424469, AL132777, BC099722

Consensus CDS

CCDS9749.2

UniProtKB/Swiss-Prot

Q4QQH5, Q4V764, Q9UIU6

Related

ENSP00000216513.4, ENST00000216513.5

Conserved Domains (2) summary

cd00086
Location:228 → 282

homeodomain; Homeodomain; DNA binding domains involved in the transcriptional regulation of key eukaryotic developmental processes; may bind to DNA as monomers or as homo- and/or heterodimers, in a sequence-specific manner.

pfam16878
Location:108 → 217

SIX1_SD; Transcriptional regulator, SIX1, N-terminal SD domain

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2025_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000014.9 Reference GRCh38.p14 Primary Assembly

Range

60709539..60724351 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_005267759.3 → XP_005267816.1 homeobox protein SIX4 isoform X1

Conserved Domains (2) summary

cd00086
Location:220 → 274

homeodomain; Homeodomain; DNA binding domains involved in the transcriptional regulation of key eukaryotic developmental processes; may bind to DNA as monomers or as homo- and/or heterodimers, in a sequence-specific manner.

pfam16878
Location:100 → 209

SIX1_SD; Transcriptional regulator, SIX1, N-terminal SD domain
XM_047431474.1 → XP_047287430.1 homeobox protein SIX4 isoform X2