Affinage

HOXA6

Homeobox protein Hox-A6 · UniProt P31267

Length
233 aa
Mass
26.3 kDa
Annotated
2026-04-28
67 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HOXA6 is a homeodomain transcription factor that specifies axial positional identity and regulates cell proliferation, survival, and migration in developmental and oncogenic contexts. Targeted disruption in mice causes homeotic posterior transformation of the seventh cervical to the first thoracic vertebra, establishing its requirement for cervicothoracic boundary specification (PMID:7918106). HOXA6 transcription is epigenetically controlled by MLL1 recruitment via the lncRNA Mistral and by EZH2-mediated H3K27me3 deposition directed through lncRNA TRERNA1, and its expression in the spinal cord is activated by SOX10 binding to the HOXA6 promoter (PMID:21925392, PMID:40640307, PMID:32428246). HOXA6 directly binds target gene promoters such as ZBTB12, physically interacts with the cofactor PBX2, and modulates PI3K/Akt/ERK signaling, Bcl-2-dependent apoptosis, and epithelial–mesenchymal transition in a tissue-dependent manner (PMID:37708965, PMID:33535170, PMID:31081053, PMID:29620285).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1994 High

    The first loss-of-function study established that HOXA6 is required for axial skeletal patterning at the cervicothoracic boundary, answering whether individual paralog group 6 HOX genes have non-redundant roles in vertebral specification.

    Evidence Gene-targeted knockout in mice with detailed skeletal analysis showing C7-to-T1 homeotic transformation

    PMID:7918106

    Open questions at the time
    • Downstream transcriptional targets mediating the skeletal transformation were not identified
    • Redundancy with other paralog group 6 members was not resolved
  2. 2009 Medium

    Gain-of-function experiments demonstrated that HOXA6 is sufficient to drive hematopoietic progenitor proliferation and self-renewal, extending its functional scope beyond skeletal patterning.

    Evidence Retroviral overexpression in FDCP-Mix and Ba/F3 hematopoietic progenitor cells with colony formation and growth-factor withdrawal assays

    PMID:19157684

    Open questions at the time
    • Direct transcriptional targets in hematopoietic cells were not identified
    • Loss-of-function confirmation in hematopoietic cells was not performed
  3. 2011 High

    Discovery of the lncRNA Mistral revealed an epigenetic activation mechanism for HOXA6 transcription, showing that a cis-encoded lncRNA recruits MLL1 to remodel chromatin at the Hoxa6 locus.

    Evidence RNA immunoprecipitation, chromatin conformation capture, MLL1 ChIP, and lncRNA knockdown/overexpression in mouse embryonic stem cells

    PMID:21925392

    Open questions at the time
    • Whether Mistral is required for HOXA6 activation in all developmental contexts was not tested
    • Structural basis of Mistral–MLL1 interaction was not resolved
  4. 2018 Medium

    Bidirectional manipulation in colorectal cancer cells showed that HOXA6 promotes proliferation, migration, and EMT while suppressing apoptosis via Bcl-2 pathway modulation, establishing its oncogenic activity in this tissue.

    Evidence Overexpression and siRNA knockdown with CCK-8, colony formation, TUNEL, Transwell, and Western blotting in Caco2 and HT-29 cells

    PMID:29620285

    Open questions at the time
    • Direct transcriptional targets driving EMT were not identified
    • In vivo tumor formation data were not provided
  5. 2019 Medium

    In contrast to colorectal cancer, HOXA6 overexpression in clear cell renal carcinoma suppressed proliferation and induced apoptosis via PI3K/Akt/ERK pathway inhibition, revealing tissue-dependent opposing roles.

    Evidence Overexpression and shRNA knockdown with Western blotting for p-Akt, p-ERK, Bcl-2, PTEN, Bax, and cleaved caspase-3 in 786-O and 769-P cells

    PMID:31081053

    Open questions at the time
    • Direct promoter occupancy by HOXA6 on PI3K/Akt pathway components was not tested
    • Mechanism determining tissue-specific tumor-suppressive versus oncogenic activity is unknown
  6. 2020 Medium

    Identification of SOX10 as an upstream transcriptional activator of HOXA6 in spinal dorsal horn neurons placed HOXA6 within a TET1–SOX10 epigenetic cascade contributing to neuropathic pain.

    Evidence ChIP confirming SOX10 binding to HOXA6 promoter, bisulfite sequencing, siRNA knockdown, AAV overexpression, and behavioral pain assays in oxaliplatin-treated rats

    PMID:32428246

    Open questions at the time
    • Direct HOXA6 transcriptional targets in nociceptive neurons were not defined
    • Whether HOXA6 is necessary for allodynia was not tested by direct Hoxa6 knockout
  7. 2021 Medium

    Co-immunoprecipitation revealed that HOXA6 physically interacts with and stabilizes PBX2, identifying a cofactor partnership that promotes metastasis in gastric cancer.

    Evidence Co-IP, siRNA knockdown, and orthotopic implantation metastasis model in gastric cancer cells

    PMID:33535170

    Open questions at the time
    • Reciprocal Co-IP and endogenous interaction confirmation were not independently replicated
    • DNA-binding specificity changes conferred by the HOXA6–PBX2 complex were not mapped
  8. 2023 Medium

    ChIP and luciferase assays demonstrated that HOXA6 directly binds and transcriptionally activates the ZBTB12 promoter in cancer-associated fibroblasts, identifying a bona fide direct target gene.

    Evidence ChIP assay, luciferase reporter, and siRNA knockdown in gastric CAFs and 293T cells

    PMID:37708965

    Open questions at the time
    • Genome-wide binding profile (ChIP-seq) for HOXA6 has not been reported
    • ZBTB12 downstream effectors mediating the pro-tumorigenic phenotype are unknown
  9. 2025 Medium

    An EZH2-mediated silencing mechanism was delineated whereby lncRNA TRERNA1 recruits EZH2 to the HOXA6 promoter to deposit H3K27me3, providing a second epigenetic regulatory axis (repressive) complementing the activating Mistral/MLL1 axis.

    Evidence ChIP for EZH2 and H3K27me3 at HOXA6 promoter, RIP for m6A-modified TRERNA1, epistasis experiments, and xenograft in NSCLC cells

    PMID:40640307

    Open questions at the time
    • Interplay between Mistral-mediated activation and TRERNA1/EZH2-mediated repression at the same locus has not been studied
    • Whether this epigenetic switch operates in normal tissues is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A genome-wide map of HOXA6 direct transcriptional targets and the structural basis for its cofactor selectivity (e.g., PBX2 versus other TALE partners) remain undefined, preventing a unified model of its tissue-specific oncogenic versus tumor-suppressive activities.
  • No ChIP-seq or CUT&RUN data for HOXA6 in any system
  • Mechanism underlying context-dependent tumor-suppressive versus oncogenic behavior is unresolved
  • Role in adult homeostasis outside cancer settings is largely unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-162582 Signal Transduction 2 R-HSA-4839726 Chromatin organization 2 R-HSA-1266738 Developmental Biology 1
Partners
EZH2MLL1PBX2SOX10ZBTB12

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 Targeted disruption of hoxa-6 in mice results in homeotic posterior transformation of the seventh cervical vertebra to the first thoracic vertebra, demonstrating Hoxa-6 is required for axial skeletal identity specification at positions approximating the anterior border of its expression domain in the prevertebrae. Gene targeting/knockout in mice with skeletal phenotype analysis Mechanisms of development High 7918106
2011 The lncRNA Mistral (Mira), encoded in the spacer DNA between Hoxa6 and Hoxa7, activates Hoxa6 and Hoxa7 transcription by recruiting the epigenetic activator MLL1 to chromatin, inducing dynamic changes in chromosome conformation. RNA immunoprecipitation, chromatin conformation capture, lncRNA knockdown and overexpression, MLL1 ChIP in mouse embryonic stem cells Molecular cell High 21925392
2009 Enforced overexpression of HOXA6 in hematopoietic FDCP-Mix progenitor cells increases proliferation, colony formation, and potentiates factor-independent proliferation in Ba/F3 cells, demonstrating a direct role for HOXA6 in hematopoietic progenitor cell self-renewal and proliferation. Retroviral overexpression, colony formation assay, growth factor withdrawal assay in primary and cell line hematopoietic progenitors Experimental hematology Medium 19157684
2021 HOXA6 physically interacts with and stabilizes the PBX2 protein in gastric cancer cells; HOXA6 and PBX2 cooperate to promote cell migration, invasion, and metastasis in vitro and in vivo. Co-immunoprecipitation, STRING database interaction prediction, siRNA knockdown, orthotopic implantation in vivo Aging Medium 33535170
2019 HOXA6 overexpression in clear cell renal cell carcinoma cells inhibits proliferation and induces apoptosis by suppressing the PI3K/Akt/ERK signaling pathway, reducing p-Akt, p-ERK and Bcl-2 levels while increasing PTEN, Bax and cleaved caspase-3. Plasmid overexpression and shRNA knockdown, Western blotting, flow cytometry, CCK-8 assay in 786-O and 769-P ccRCC cell lines International journal of oncology Medium 31081053
2018 HOXA6 promotes colorectal cancer cell proliferation, migration, and invasion while inhibiting apoptosis; it regulates apoptosis through the Bcl-2 pathway and promotes migration/invasion through induction of epithelial-mesenchymal transition (suppressing E-cadherin, upregulating N-cadherin and Vimentin). Plasmid overexpression and siRNA knockdown, CCK-8, colony formation, TUNEL, Transwell, wound-healing assays, Western blotting in Caco2 and HT-29 cells International journal of oncology Medium 29620285
2020 HOXA6 is upregulated in the spinal dorsal horn following oxaliplatin treatment downstream of SOX10: TET1-mediated demethylation of the SOX10 promoter leads to SOX10 upregulation, which then binds the HOXA6 promoter to drive HOXA6 transcription, contributing to mechanical allodynia. siRNA knockdown, reduced representation bisulfite sequencing, chromatin immunoprecipitation, AAV overexpression, behavioral pain assays in rat model International journal of cancer Medium 32428246
2023 HOXA6 transcriptionally activates ZBTB12 by binding to its promoter in gastric cancer-associated fibroblasts (CAFs), and this HOXA6-ZBTB12 axis promotes gastric cancer cell growth, migration, and invasiveness. ChIP assay confirming HOXA6 binding to ZBTB12 promoter, siRNA knockdown, luciferase reporter assay in 293T cells and CAFs Acta pharmaceutica (Zagreb, Croatia) Medium 37708965
2025 DDR1 promotes bladder cancer progression by targeting HOXA6 to inhibit ferroptosis; DDR1 knockdown-induced ferroptosis was rescued by HOXA6 knockdown, placing HOXA6 downstream of DDR1 in a pathway that maintains GSH, GPX4, and SLC7A11 levels and suppresses lipid peroxidation. siRNA knockdown, in vitro and in vivo functional assays, Western blotting for ferroptosis markers in bladder cancer cells Journal of cellular and molecular medicine Low 40105492
2024 Hoxa6 is differentially expressed in enteric neuronal lineages during enteric nervous system development; in Sox10Dom/+ Hirschsprung mouse mutants, Hoxa6 expression is altered in early developing neurons, implicating Hoxa6 in enteric neuron lineage allocation downstream of Sox10. Single-cell RNA sequencing, hybridization chain reaction (HCR) validation, gene regulatory network analysis in Sox10Dom/+ mouse ENS bioRxivpreprint Low 39345473
2025 KIAA1429 (VIRMA) promotes NSCLC cell proliferation through lncRNA TRERNA1, which recruits EZH2 to the HOXA6 promoter, increasing H3K27me3 modification and suppressing HOXA6 expression; HOXA6 downregulation is required for KIAA1429-driven proliferation. RIP assay for m6A on TRERNA1, ChIP for EZH2 and H3K27me3 at HOXA6 promoter, siRNA/overexpression epistasis experiments, in vivo xenograft Scientific reports Medium 40640307

Source papers

Stage 0 corpus · 67 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature 755 1673020
1991 Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell 637 1680563
1992 Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature 481 1346922
1990 Variations of cervical vertebrae after expression of a Hox-1.1 transgene in mice. Cell 347 1970515
1993 Loss of Hox-A1 (Hox-1.6) function results in the reorganization of the murine hindbrain. Development (Cambridge, England) 309 7903632
1992 Identification of a retinoic acid responsive enhancer 3' of the murine homeobox gene Hox-1.6. Mechanisms of development 245 1360810
1989 Craniofacial abnormalities induced by ectopic expression of the homeobox gene Hox-1.1 in transgenic mice. Cell 240 2568891
1990 The segment-specific gene Krox-20 encodes a transcription factor with binding sites in the promoter region of the Hox-1.4 gene. The EMBO journal 190 1969796
2011 The noncoding RNA Mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin. Molecular cell 185 21925392
1989 Transgenic mice overexpressing the mouse homoeobox-containing gene Hox-1.4 exhibit abnormal gut development. Nature 185 2563568
1989 Mouse homeo-genes within a subfamily, Hox-1.4, -2.6 and -5.1, display similar anteroposterior domains of expression in the embryo, but show stage- and tissue-dependent differences in their regulation. Development (Cambridge, England) 184 2576400
1993 Specification of axial identity in the mouse: role of the Hoxa-5 (Hox1.3) gene. Genes & development 167 7901120
1988 Mouse homeobox gene transcripts occupy different but overlapping domains in embryonic germ layers and organs: a comparison of Hox-3.1 and Hox-1.5. Development (Cambridge, England) 134 2904354
1993 The establishment of murine Hox-1 expression domains during patterning of the limb. Developmental biology 131 8099045
1989 The Hox-1.3 homeo box protein is a sequence-specific DNA-binding phosphoprotein. Genes & development 130 2565857
1987 Hox-1.6: a mouse homeo-box-containing gene member of the Hox-1 complex. The EMBO journal 118 2891503
1986 A new homeo-box is present in overlapping cosmid clones which define the mouse Hox-1 locus. The EMBO journal 118 3019676
1993 The mouse Hox-1.3 gene is functionally equivalent to the Drosophila Sex combs reduced gene. Genes & development 110 8095481
1987 Differential expression of the mouse homeobox-containing gene Hox-1.4 during male germ cell differentiation and embryonic development. Proceedings of the National Academy of Sciences of the United States of America 104 2441396
1994 Targeted disruptions of the murine Hoxa-4 and Hoxa-6 genes result in homeotic transformations of components of the vertebral column. Mechanisms of development 102 7918106
1991 Separate elements cause lineage restriction and specify boundaries of Hox-1.1 expression. Development (Cambridge, England) 101 1685116
1989 The mouse Hox-1.4 gene: primary structure, evidence for promoter activity and expression during development. Development (Cambridge, England) 101 2576648
1987 Homoeobox gene Hox-1.5 expression in mouse embryos: earliest detection by in situ hybridization is during gastrulation. Development (Cambridge, England) 98 2452725
1993 Sequences 5' of the homeobox of the Hox-1.4 gene direct tissue-specific expression of lacZ during mouse development. Development (Cambridge, England) 91 8100763
2004 Retinoic acid signaling acts via Hox1 to establish the posterior limit of the pharynx in the chordate amphioxus. Development (Cambridge, England) 88 15576409
1990 Position-specific activity of the Hox1.1 promoter in transgenic mice. Development (Cambridge, England) 75 1971214
2006 Reversal of Hox1 gene subfunctionalization in the mouse. Developmental cell 74 16890163
1987 Murine Hox-1.7 homeo-box gene: cloning, chromosomal location, and expression. Molecular and cellular biology 74 2891029
1988 Differential expression of the homeobox gene Hox-1.3 in F9 embryonal carcinoma cells. Proceedings of the National Academy of Sciences of the United States of America 66 2456573
1992 Murine Hox-1.11 homeobox gene structure and expression. Proceedings of the National Academy of Sciences of the United States of America 59 1352886
2003 Expression of Raldh2, Cyp26 and Hox-1 in normal and retinoic acid-treated Ciona intestinalis embryos. Gene expression patterns : GEP 56 12799071
2002 Conserved regulation of the Caenorhabditis elegans labial/Hox1 gene ceh-13. Developmental biology 53 11820809
1987 A mouse homeo box gene, Hox-1.5, and the morphological locus, Hd, map to within 1 cM on chromosome 6. Genetics 49 2887485
1991 Isolation and mapping of EVX1, a human homeobox gene homologous to even-skipped, localized at the 5' end of HOX1 locus on chromosome 7. Nucleic acids research 45 1684419
2012 Retinoic acid-driven Hox1 is required in the epidermis for forming the otic/atrial placodes during ascidian metamorphosis. Development (Cambridge, England) 42 22573621
1988 Genetic analysis and developmental regulation of testis-specific RNA expression of Mos, Abl, actin and Hox-1.4. Oncogene 42 2895445
2019 Study of Promoter Methylation Patterns of HOXA2, HOXA5, and HOXA6 and Its Clinicopathological Characteristics in Colorectal Cancer. Frontiers in oncology 34 31165042
2005 Identification and linkage mapping of the genes for the putative homeodomain protein (hox1) and the putative pheromone receptor protein homologue (rcb1) in a bipolar basidiomycete, Pholiota nameko. Current genetics 32 16096791
2007 Relationship between COPD and polymorphisms of HOX-1 and mEPH in a Chinese population. Oncology reports 28 17203192
1993 Conservation and divergence of patterns of expression and lineage-specific transcripts in orthologues and paralogues of the mouse Hox-1.4 gene. Developmental biology 27 7680626
2008 Evolution of the thyroid: anterior-posterior regionalization of the Oikopleura endostyle revealed by Otx, Pax2/5/8, and Hox1 expression. Developmental dynamics : an official publication of the American Association of Anatomists 25 18386819
2009 Epidermal expression of Hox1 is directly activated by retinoic acid in the Ciona intestinalis embryo. Developmental biology 24 19782671
2019 HOXA6 inhibits cell proliferation and induces apoptosis by suppressing the PI3K/Akt signaling pathway in clear cell renal cell carcinoma. International journal of oncology 20 31081053
2019 MiR-1294 acts as a tumor suppressor in clear cell renal cell carcinoma through targeting HOXA6. European review for medical and pharmacological sciences 19 31114997
2009 Hoxa6 potentiates short-term hemopoietic cell proliferation and extended self-renewal. Experimental hematology 19 19157684
1992 Hox-1.11 and Hox-4.9 homeobox genes. Proceedings of the National Academy of Sciences of the United States of America 19 1348361
2018 Effect of HOXA6 on the proliferation, apoptosis, migration and invasion of colorectal cancer cells. International journal of oncology 18 29620285
2020 A six-amino-acid motif is a major determinant in functional evolution of HOX1 proteins. Genes & development 16 33184220
2021 Coexpression of HOXA6 and PBX2 promotes metastasis in gastric cancer. Aging 15 33535170
2020 Oxaliplatin-induced neuropathic pain involves HOXA6 via a TET1-dependent demethylation of the SOX10 promoter. International journal of cancer 15 32428246
1990 Alternatively spliced Hox-1.7 transcripts encode different protein products. DNA sequence : the journal of DNA sequencing and mapping 15 1983703
2022 Next-generation sequencing identifies HOXA6 as a novel oncogenic gene in low grade glioma. Aging 13 35349479
1989 Progressive restriction in the distribution of the Hox-1.3 homeodomain protein during embryogenesis. Journal of neuroscience research 13 2689656
2013 Identification of a retinoic acid-responsive neural enhancer in the Ciona intestinalis Hox1 gene. Development, growth & differentiation 9 23302037
1993 Protein product of the somatic-type transcript of the Hoxa-4 (Hox-1.4) gene binds to homeobox consensus binding sites in its promoter and intron. Journal of cellular biochemistry 8 7901228
2023 Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of the HOXA6/ZBTB12 axis. Acta pharmaceutica (Zagreb, Croatia) 7 37708965
2019 A novel long non-coding RNA from the HOXA6-HOXA5 locus facilitates colon cancer cell growth. BMC cancer 5 31159758
2010 HOX-1 and COX-2: Two differentially regulated key mediators of skeletal myoblast tolerance under oxidative stress. Free radical research 5 20370564
1991 Murine embryonic spinal cord and adult testis Hox-1.4 cDNAs are identical 3' to the homeo box. DNA sequence : the journal of DNA sequencing and mapping 5 1686835
1993 Multiple levels of regulation exist for expression of the Hoxa-4 (Hox-1.4) gene in the mouse testis. Cellular & molecular biology research 4 7909702
1995 The kinetics of induction of Hox1.6 and C-jun mRNA during three different ways of inducing differentiation in teratocarcinoma F9 cells. In vitro cellular & developmental biology. Animal 2 8589890
2025 DDR1 Targeting HOXA6 Facilitates Bladder Cancer Progression via Inhibiting Ferroptosis. Journal of cellular and molecular medicine 1 40105492
2025 KIAA1429 promotes non-small-cell lung cancer cell proliferation through the TRERNA1/HOXA6 axis. Scientific reports 1 40640307
2017 Dataset of the HOX1 gene sequences of the wheat polyploids and their diploid relatives. Data in brief 1 29201982
2024 Retraction Note: MiR-1294 acts as a tumor suppressor in clear cell renal cell carcinoma through targeting HOXA6. European review for medical and pharmacological sciences 0 38884519
2024 Single Cell Profiling in the Sox10 Hirschsprung Mouse Implicates Hoxa6 in Enteric Neuron Lineage Allocation. bioRxiv : the preprint server for biology 0 39345473
1994 Identification and promoter activity of DNase I hypersensitive sites in the region of the Hox-1.3 gene. DNA and cell biology 0 7910023