Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Abstract

Abstract Review on HOXC8, with data on DNA/RNA, on the protein encoded and functions in which this gene is implicated.

HOXC8 (homeobox C8)

Identity

Other namesHOX3
HOX3A
HGNC (Hugo) HOXC8
LocusID (NCBI) 3224
Location 12q13.13
Location_base_pair Starts at 54402890 and ends at 54406545 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Orientation: plus strand.
Note This gene is one of several homeobox HOXC genes located in a cluster on chromosome 12. The product of this gene may play a role in the regulation of cartilage differentiation (Yueh et al., 1998). It is also involved in chondrodysplasias and other cartilage disorders (Cormier et al., 2003; Kamel et al., 2009; Yueh et al., 1998).

DNA/RNA

 
  Figure 1. A. Schematic representation of human HOXC8 gene. B. Human HOXC8 protein with the indicated position of homeodomain (red color) and coiled-coil (blue color).
Description The HOXC8 gene is 3658 nucleotide long and consists of two exons. There are 112 known SNPs in HOXC8 gene and most of them locate on the 5' end of the gene.
Transcription The transcribed matured mRNA is 2290 nucleotide in length.
Transcription regulators: 1) CDX1, which is a member of the caudal-related homeobox transcription factor gene family, activates HOXC8 transcription by binding to its early enhancer (Schyr et al., 2012). 2) Activating protein 2 delta (AP2δ) transcription factor, which is one of AP2 five family members (AP2α, AP2β, AP2γ, AP2δ and AP2ε), recruits Ash2I and ALR to the HOXC8 locus, resulting in H3K4me3-mediated gene activation (Tan et al., 2008). 3) Menin, which is a tumor suppressor gene associated with a syndrome known as multiple endocrine neoplasia type 1, binds to HOXC8 locus by associating with a histone methyltransferase complex containing two trithorax family proteins, MLL2 and Ash2L (MacConaill et al., 2006). 4) GTF2IRD1, which is a TFII-I family of transcription factors, interacts with HOXC8 early enhancer and represses the gene transcription (Thompson et al., 2007).

Protein

 
  Figure 2. HOXC8 transcription can be regulated by CDX1, AP2d, menin and GTF2IRD1, respectively. The translation of HOXC8 protein can be blocked by the binding of miR-196s to its 3'UTR. As a transcription factor, HOXC8 is involved in the transcription of a variety of genes implicated in embryogenesis and tumorigenesis.
Description HOXC8 protein contains 242 amino acids and is 27755 Da. HOXC8 contains a ~60 amino acid homeodomain with helix-turn-helix (HTH) motif which functions as a DNA binding domain. HOXC8 binds to DNA as monomers or homo- and/or heterodimers in a sequence-specific manner.
Expression In mouse embryogenesis: HOXC8 is expressed in the neural tube and somatic mesoderm as well as in the prospective thorax. During embryogenesis, Hoxc8 is initially expressed with the identical boundaries in the mesoderm and neurectoderm. Subsequently, Hoxc8 expression creeps forward and the boundaries in mesoderm and neural tube diverge. The gene is also expressed in both the neural tube and the somites in the prospective thorax (Pollock et al., 1992; Shashikant and Ruddle, 1996).
Cancers: Elevated HOXC8 expression is detected in breast cancer (Li et al., 2014; Li et al., 2010), cervical cancer (Alami et al., 1999), prostate cancer (Waltregny et al., 2002), esophageal cancer (Du et al., 2014), pancreatic cancer (Adwan et al., 2011).
Organs: HOXC8 is expressed in hematopoietic organs, brain, breast, placenta, liver, bone marrow, kidney, intestine and nervous systems, etc.
Cell types: HOXC8 is expressed on a variety of cell types, including fibroblasts, neurons, hair, adipose, skeletal and smooth muscle cells, lymph T cells, endothelial and epithelial cells, mesenchymal and stem cells, etc.
Translation regulation: Members of microRNA 196 family (miR-196a1, miR-196a2 and miR-196b) can bind to the 3'-UTR of HOXC8 mRNA, leading to the repression of HOXC8 translation (Li et al., 2010).
Localisation Nucleus.
Function HOXC8 serves as a transcription factor to regulate the expression of genes that are implicated in skeletal and neural development in embryogenesis and cancer progression.
Embryogenesis: Like other HOX proteins, HOXC8 plays an essential role in embryo anterior-posterior patterning and is responsible for skeletal and neural development (Juan et al., 2006; Thickett and Morgan, 2002). Null mutants of HOXC8 show neuromuscular defects in the forelimb and skeletal defects in the ribs and vertebrae of the thorax (Le Mouellic et al., 1992). Overexpression of a Hoxc8 transgene has been shown to cause cartilage defects by inhibiting the maturation and stimulating the proliferation of chondrocytes (Yueh et al., 1998).
Transcriptional regulation: As a transcription factor, microarray data indicate that HOXC8 regulates the expression of genes that are involved in cell proliferation, migration, adhesion, and differentiation (Lei et al., 2005). In response to bone morphogenetic protein (BMP) stimulation, HOXC8 activates the transcription of osteopontin (OPN) by interacting with Smad1 (Shi et al., 1999). In breast cancer cells, HOXC8 functions as a transcription factor to regulate cadherin 11 (Cdh11) transcription (Li et al., 2014; Li et al., 2011). ChIP assays demonstrate that HOXC8 can bind to the promoter of target genes including NCAM (neural cell adhesion molecule), PEDF (pigment epithelium-derived factor), ZAC1 (the zinc finger protein regulator of apoptosis) and PCNA (proliferating cell nuclear antigen) (Lei et al., 2006; Min et al., 2010). In addition, HOXC8 has also been identified as a transcription repressor. For instance, HOXC8 can downregulate the expression of Mgl1 and Smad6 by directly binding to the promoter regions of these 2 genes (Kang et al., 2010; Ruthala et al., 2011).
Stem cells: HOXC8 is expressed in vascular wall-resident multi-potent stem cells (VW-MPSCs), and silencing its expression significantly reduces cell sprouting capacity and increases expression of the smooth muscle cells marker genes (Klein et al., 2013).
Cancers: HOXC8 plays an essential role in cancer development, including breast, prostate, cervical and pancreatic cancers by facilitating cell migration and invasion (Adwan et al., 2011; Alami et al., 1999; Axlund et al., 2010; Du et al., 2014; Li et al., 2010).

Implicated in

Entity Breast cancer
Note Elevated expression of HOXC8 is found in invasive breast cell lines when compared with noninvasive breast cell lines. Immunohistochemistry staining shows that the level of HOXC8 is higher in breast cancer tissues than normal breast tissues (Li et al., 2010). Ectopic HOXC8 expression induces Cdh11 expression and promotes breast tumorigenesis (Li et al., 2012). Importantly, forced Cdh11 expression reverses the inhibitory effect in breast tumorigenesis elicited by HOXC8 knockdown (Li et al., 2014). Moreover, the analysis of publically available human breast tumor microarray gene expression database demonstrates a strong positive linear association between HOXC8 and CDH11 expression (R = 0.801, p < 0.001). Survival analysis (Kaplan-Meier method, log-rank test) show that both high HOXC8 and CDH11 expression correlates with poor recurrence-free survival rate of patients (Li et al., 2014). Together, these findings suggest that HOXC8 promotes breast tumorigenesis by maintaining high level of CDH11 expression in breast cancer cells.
  
Entity Prostate cancer
Note HOXC8 is upregulated in primary prostate tumors, lymph node metastases and malignant prostate cell lines. HOXC8 overexpression has also been found to be correlated with loss of differentiation in prostate cancer cell lines and higher Gleason grade in prostate tissues. These observations suggest that HOXC8 plays a role in the acquisition of invasion and metastasis of prostate cancer (Miller et al., 2003; Waltregny et al., 2002).
  
Entity Pancreatic cancer
Note In human pancreatic cancer cell lines, the level of HOXC8 mRNA is inversely related to their growth. Down-regulation of HOXC8 expression causes increased proliferation, migration and colony formation, which indicates that HOXC8 is a negative regulator of pancreatic cancer cell growth and metastasis. In primary and metastatic tumor samples, immunohistochemistry staining shows that grading of primary carcinomas is negatively associated with the extent and intensity of HOXC8 staining (Adwan et al., 2011).
  
Entity Cervical cancer
Note The expression of HOXC8 is turned in in human cervical cancer cells while is off in normal cervical keratinocytes. This observation indicates that HOXC8 is probably involved in the process of cervical keratinocytes transformation (Alami et al., 1999).
  
Entity Esophageal cancer
Note Immunohistochemistry staining of 274 patients' tissues with esophageal squamous cell carcinoma (ESCC) show that HOXC8 expression has a strong correlation with 5-year survival rate and increases significantly from TNM (tumor & regional lymph node & metastasis) stage I to TNM stage III. This study indicates that HOXC8 expression may be used as prognostic markers in patients with ESCC (Du et al., 2014).
  

External links

Nomenclature
HGNC (Hugo)HOXC8   5129
Cards
AtlasHOXC8ID45912ch12q13
Entrez_Gene (NCBI)HOXC8  3224  homeobox C8
GeneCards (Weizmann)HOXC8
Ensembl hg19 (Hinxton) [Gene_View]  chr12:54402890-54406545 [Contig_View]  HOXC8 [Vega]
Ensembl hg38 (Hinxton) [Gene_View]  chr12:54402890-54406545 [Contig_View]  HOXC8 [Vega]
cBioPortalHOXC8
AceView (NCBI)HOXC8
Genatlas (Paris)HOXC8
WikiGenes3224
SOURCE (Princeton)HOXC8
Genomic and cartography
GoldenPath hg19 (UCSC)HOXC8  -     chr12:54402890-54406545 +  12q13.13   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)HOXC8  -     12q13.13   [Description]    (hg38-Dec_2013)
EnsemblHOXC8 - 12q13.13 [CytoView hg19]  HOXC8 - 12q13.13 [CytoView hg38]
Mapping of homologs : NCBIHOXC8 [Mapview hg19]  HOXC8 [Mapview hg38]
OMIM142970   
Gene and transcription
Genbank (Entrez)AK290959 BC053898 BU156590 BU618342 X99680
RefSeq transcript (Entrez)NM_022658
RefSeq genomic (Entrez)AC_000144 NC_000012 NC_018923 NT_029419 NW_001838059 NW_004929384
Consensus coding sequences : CCDS (NCBI)HOXC8
Cluster EST : UnigeneHs.664500 [ NCBI ]
CGAP (NCI)Hs.664500
Alternative Splicing : Fast-db (Paris)GSHG0006705
Gene ExpressionHOXC8 [ NCBI-GEO ]     HOXC8 [ SEEK ]   HOXC8 [ MEM ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP31273 (Uniprot)
NextProtP31273  [Medical]
With graphics : InterProP31273
Splice isoforms : SwissVarP31273 (Swissvar)
Domaine pattern : Prosite (Expaxy)ANTENNAPEDIA (PS00032)    HOMEOBOX_1 (PS00027)    HOMEOBOX_2 (PS50071)   
Domains : Interpro (EBI)Homeobox_Antennapedia_CS    Homeobox_CS    Homeobox_dom    Homeobox_metazoa    Homeodomain-like    HTH_motif   
Related proteins : CluSTrP31273
Domain families : Pfam (Sanger)Homeobox (PF00046)   
Domain families : Pfam (NCBI)pfam00046   
Domain families : Smart (EMBL)HOX (SM00389)  
DMDM Disease mutations3224
Blocks (Seattle)P31273
Peptide AtlasP31273
HPRD00856
IPIIPI00010756   
Protein Interaction databases
DIP (DOE-UCLA)P31273
IntAct (EBI)P31273
BioGRIDHOXC8
IntegromeDBHOXC8
STRING (EMBL)HOXC8
Ontologies - Pathways
QuickGOP31273
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  transcription regulatory region sequence-specific DNA binding  sequence-specific DNA binding transcription factor activity  nucleus  nucleolus  transcription, DNA-templated  anterior/posterior pattern specification  microtubule cytoskeleton  neuron differentiation  skeletal system morphogenesis  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  transcription regulatory region sequence-specific DNA binding  sequence-specific DNA binding transcription factor activity  nucleus  nucleolus  transcription, DNA-templated  anterior/posterior pattern specification  microtubule cytoskeleton  neuron differentiation  skeletal system morphogenesis  
Protein Interaction DatabaseHOXC8
DoCM (Curated mutations)HOXC8
Wikipedia pathwaysHOXC8
Gene fusion - rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerHOXC8 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)HOXC8
dbVarHOXC8
ClinVarHOXC8
1000_GenomesHOXC8 
Exome Variant ServerHOXC8
SNP (GeneSNP Utah)HOXC8
SNP : HGBaseHOXC8
Genetic variants : HAPMAPHOXC8
Genomic VariantsHOXC8  HOXC8 [DGVbeta]
Mutations
Somatic Mutations in Cancer : COSMICHOXC8 
CONAN: Copy Number AnalysisHOXC8 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)12:54402890-54406545
Mutations and Diseases : HGMDHOXC8
OMIM142970   
MedgenHOXC8
NextProtP31273 [Medical]
GENETestsHOXC8
Disease Genetic AssociationHOXC8
Huge Navigator HOXC8 [HugePedia]  HOXC8 [HugeCancerGEM]
snp3D : Map Gene to Disease3224
DGIdb (Drug Gene Interaction db)HOXC8
General knowledge
Homologs : HomoloGeneHOXC8
Homology/Alignments : Family Browser (UCSC)HOXC8
Phylogenetic Trees/Animal Genes : TreeFamHOXC8
Chemical/Protein Interactions : CTD3224
Chemical/Pharm GKB GenePA29404
Clinical trialHOXC8
Other databases
Probes
Litterature
PubMed29 Pubmed reference(s) in Entrez
CoreMineHOXC8
GoPubMedHOXC8
iHOPHOXC8

Bibliography

Homeosis in the mouse induced by a null mutation in the Hox-3.1 gene.
Le Mouellic H, Lallemand Y, Brulet P.
Cell. 1992 Apr 17;69(2):251-64.
PMID 1348969
 
Altering the boundaries of Hox3.1 expression: evidence for antipodal gene regulation.
Pollock RA, Jay G, Bieberich CJ.
Cell. 1992 Dec 11;71(6):911-23.
PMID 1360875
 
Combinations of closely situated cis-acting elements determine tissue-specific patterns and anterior extent of early Hoxc8 expression.
Shashikant CS, Ruddle FH.
Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12364-9.
PMID 8901587
 
Evidence for regulation of cartilage differentiation by the homeobox gene Hoxc-8.
Yueh YG, Gardner DP, Kappen C.
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9956-61.
PMID 9707582
 
HOXC5 and HOXC8 expression are selectively turned on in human cervical cancer cells compared to normal keratinocytes.
Alami Y, Castronovo V, Belotti D, Flagiello D, Clausse N.
Biochem Biophys Res Commun. 1999 Apr 21;257(3):738-45.
PMID 10208853
 
Smad1 interacts with homeobox DNA-binding proteins in bone morphogenetic protein signaling.
Shi X, Yang X, Chen D, Chang Z, Cao X.
J Biol Chem. 1999 May 7;274(19):13711-7.
PMID 10224145
 
Hoxc-8 expression shows left-right asymmetry in the posterior lateral plate mesoderm.
Thickett C, Morgan R.
Gene Expr Patterns. 2002 Nov;2(1-2):5-6.
PMID 12617829
 
Overexpression of the homeobox gene HOXC8 in human prostate cancer correlates with loss of tumor differentiation.
Waltregny D, Alami Y, Clausse N, de Leval J, Castronovo V.
Prostate. 2002 Feb 15;50(3):162-9.
PMID 11813208
 
Normal proliferation and differentiation of Hoxc-8 transgenic chondrocytes in vitro.
Cormier SA, Mello MA, Kappen C.
BMC Dev Biol. 2003 Apr 24;3:4. Epub 2003 Apr 24.
PMID 12713673
 
Aberrant HOXC expression accompanies the malignant phenotype in human prostate.
Miller GJ, Miller HL, van Bokhoven A, Lambert JR, Werahera PN, Schirripa O, Lucia MS, Nordeen SK.
Cancer Res. 2003 Sep 15;63(18):5879-88.
PMID 14522913
 
The identification of Hoxc8 target genes.
Lei H, Wang H, Juan AH, Ruddle FH.
Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2420-4. Epub 2005 Feb 7.
PMID 15699330
 
Multiple roles of hoxc8 in skeletal development.
Juan AH, Lei H, Bhargava P, Lebrun M, Ruddle FH.
Ann N Y Acad Sci. 2006 Apr;1068:87-94.
PMID 16831908
 
Identification of a Hoxc8-regulated transcriptional network in mouse embryo fibroblast cells.
Lei H, Juan AH, Kim MS, Ruddle FH.
Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10305-9. Epub 2006 Jun 22.
PMID 16793922
 
Phosphorylation of the menin tumor suppressor protein on serine 543 and serine 583.
MacConaill LE, Hughes CM, Rozenblatt-Rosen O, Nannepaga S, Meyerson M.
Mol Cancer Res. 2006 Oct;4(10):793-801.
PMID 17050672
 
GTF2IRD1 regulates transcription by binding an evolutionarily conserved DNA motif 'GUCE'.
Thompson PD, Webb M, Beckett W, Hinsley T, Jowitt T, Sharrocks AD, Tassabehji M.
FEBS Lett. 2007 Mar 20;581(6):1233-42. Epub 2007 Feb 28.
PMID 17346708
 
Transcription factor Ap2delta associates with Ash2l and ALR, a trithorax family histone methyltransferase, to activate Hoxc8 transcription.
Tan CC, Sindhu KV, Li S, Nishio H, Stoller JZ, Oishi K, Puttreddy S, Lee TJ, Epstein JA, Walsh MJ, Gelb BD.
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7472-7. doi: 10.1073/pnas.0711896105. Epub 2008 May 21.
PMID 18495928
 
Morpholino-mediated knockdown in primary chondrocytes implicates Hoxc8 in regulation of cell cycle progression.
Kamel S, Kruger C, Salbaum JM, Kappen C.
Bone. 2009 Apr;44(4):708-16. doi: 10.1016/j.bone.2008.10.057. Epub 2008 Nov 21.
PMID 19071237
 
HOXC8 inhibits androgen receptor signaling in human prostate cancer cells by inhibiting SRC-3 recruitment to direct androgen target genes.
Axlund SD, Lambert JR, Nordeen SK.
Mol Cancer Res. 2010 Dec;8(12):1643-55. doi: 10.1158/1541-7786.MCR-10-0111. Epub 2010 Nov 2.
PMID 21047772
 
Hoxc8 represses BMP-induced expression of Smad6.
Kang M, Bok J, Deocaris CC, Park HW, Kim MH.
Mol Cells. 2010 Jan;29(1):29-33. doi: 10.1007/s10059-010-0007-1. Epub 2009 Dec 7.
PMID 20016939
 
Ratio of miR-196s to HOXC8 messenger RNA correlates with breast cancer cell migration and metastasis.
Li Y, Zhang M, Chen H, Dong Z, Ganapathy V, Thangaraju M, Huang S.
Cancer Res. 2010 Oct 15;70(20):7894-904. doi: 10.1158/0008-5472.CAN-10-1675. Epub 2010 Aug 24.
PMID 20736365
 
Proliferating cell nuclear antigen (Pcna) as a direct downstream target gene of Hoxc8.
Min H, Lee JY, Bok J, Chung HJ, Kim MH.
Biochem Biophys Res Commun. 2010 Feb 19;392(4):543-7. doi: 10.1016/j.bbrc.2010.01.059. Epub 2010 Jan 25.
PMID 20097160
 
Expression of HOXC8 is inversely related to the progression and metastasis of pancreatic ductal adenocarcinoma.
Adwan H, Zhivkova-Galunska M, Georges R, Eyol E, Kleeff J, Giese NA, Friess H, Bergmann F, Berger MR.
Br J Cancer. 2011 Jul 12;105(2):288-95. doi: 10.1038/bjc.2011.217. Epub 2011 Jun 28.
PMID 21712827
 
HOXC8-Dependent Cadherin 11 Expression Facilitates Breast Cancer Cell Migration through Trio and Rac.
Li Y, Guo Z, Chen H, Dong Z, Pan ZK, Ding H, Su SB, Huang S.
Genes Cancer. 2011 Sep;2(9):880-8. doi: 10.1177/1947601911433129.
PMID 22593800
 
Hoxc8 downregulates Mgl1 tumor suppressor gene expression and reduces its concomitant function on cell adhesion.
Ruthala K, Gadi J, Lee JY, Yoon H, Chung HJ, Kim MH.
Mol Cells. 2011 Sep;32(3):273-9. doi: 10.1007/s10059-011-0069-8. Epub 2011 Jul 15.
PMID 21773674
 
Cdx1 is essential for the initiation of HoxC8 expression during early embryogenesis.
Schyr RB, Shabtai Y, Shashikant CS, Fainsod A.
FASEB J. 2012 Jun;26(6):2674-84. doi: 10.1096/fj.11-191403. Epub 2012 Mar 16.
PMID 22426122
 
Hox genes are involved in vascular wall-resident multipotent stem cell differentiation into smooth muscle cells.
Klein D, Benchellal M, Kleff V, Jakob HG, Ergun S.
Sci Rep. 2013 Oct 22;3:2178. doi: 10.1038/srep02178.
PMID 24145756
 
The survival predictive significance of HOXC6 and HOXC8 in esophageal squamous cell carcinoma.
Du YB, Dong B, Shen LY, Yan WP, Dai L, Xiong HC, Liang Z, Kang XZ, Qin B, Chen KN.
J Surg Res. 2014 May 15;188(2):442-50. doi: 10.1016/j.jss.2014.01.017. Epub 2014 Jan 17.
PMID 24525058
 
HOXC8 promotes breast tumorigenesis by transcriptionally facilitating cadherin-11 expression.
Li Y, Chao F, Huang B, Liu D, Kim J, Huang S.
Oncotarget. 2014 May 15;5(9):2596-607.
PMID 24810778
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

Contributor(s)

Written07-2014Shuang Huang, Yong Li
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, 1414 Laney Walker Blvd, Augusta, GA 30912, USA (SH); Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei, Anhui, China (YL)

Citation

This paper should be referenced as such :
Huang S, Li Y
HOXC8 (homeobox C8);
Atlas Genet Cytogenet Oncol Haematol. July 2014
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/HOXC8ID45912ch12q13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Sun Dec 21 03:29:22 CET 2014

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.