|Gene:||HOXC10; homeobox C10|
|Aliases: || HOX3I |
|Summary:||This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms. Mammals possess four similar homeobox gene clusters, HOXA, HOXB, HOXC and HOXD, which are located on different chromosomes and consist of 9 to 11 genes arranged in tandem. This gene is one of several homeobox HOXC genes located in a cluster on chromosome 12. The protein level is controlled during cell differentiation and proliferation, which may indicate this protein has a role in origin activation. [provided by RefSeq, Jul 2008]|
|Databases:||OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene|
|Protein:||homeobox protein Hox-C10|
|Updated:||14 December, 2014|
What does this gene/protein do?
Graph generated 14 December 2014 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex
Scope includes mutations and abnormal protein expression.
|Breast Cancer||HOXC10 Silencing in ER positive Breast Cancer Epigenetics|
Aromatase inhibitors (AI) are use in the treatment of estrogen receptor (ER) positive breast cancer, but tumors often develop resistance to these. Pathiraja et al (2014) identified ways in which cancer cells develop this resistance by 'epigenic reprogramming' - using the mechanisms for ‘switching off ‘ genes seen in normal cells as they differentiate and take on specialist functions. The NIH-funded study found methylation of DNA (in a 'CpG shore' which overlapped with a ER binding site) resulting in reduced expression of the HOXC10 gene in breast cancer cell lines. Even when ER signaling was blocked in cell lines and tumors this only resulted in short-term HOXC10 expression and the cells went on to increas DNA methylation and silencing of HOXC10.
The study linked reduced HOXC10 with decreased apoptosis and caused antiestrogen resistance. An analysis of paired primary and metastatic breast cancer specimens showed HOXC10 was reduced in tumors that recurred during AI treatment.
Drawing on this study and previous work the authors propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival. AI treatments induce these genes to cause short-term apoptosis and clinical benefit, but long-term AI treatment results in permanent repression of these genes via methylation resulting in resistance. Therefore the authors propose future investigation of therapies aimed at inhibiting AI-induced histone and DNA methylation in order to block or slow down AI resistance.
Pathiraja TN, Nayak SR, Xi Y, et al. Epigenetic Reprogramming of HOXC10 in Endocrine-Resistant Breast Cancer Sci. Transl. Med. 6, 229ra41 (2014).
| View Publications||0|
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: HOXC10 (cancer-related)
Pathiraja TN, Nayak SR, Xi Y, et al.Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer.
Sci Transl Med. 2014; 6(229):229ra41 [PubMed
] Related Publications
Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)-positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with enrichment for promoter hypermethylation of developmental genes. For the homeobox gene HOXC10, methylation occurred in a CpG shore, which overlapped with a functional ER binding site, causing repression of HOXC10 expression. Although short-term blockade of ER signaling caused relief of HOXC10 repression in both cell lines and breast tumors, it also resulted in concurrent recruitment of EZH2 and increased H3K27me3, ultimately transitioning to increased DNA methylation and silencing of HOXC10. Reduced HOXC10 in vitro and in xenografts resulted in decreased apoptosis and caused antiestrogen resistance. Supporting this, we used paired primary and metastatic breast cancer specimens to show that HOXC10 was reduced in tumors that recurred during AI treatment. We propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival, whereas AIs induce these genes to cause apoptosis and therapeutic benefit, but long-term AI treatment results in permanent repression of these genes via methylation and confers resistance. Therapies aimed at inhibiting AI-induced histone and DNA methylation may be beneficial in blocking or delaying AI resistance.Related: Apoptosis Breast Cancer
We recently reported a role of polycomb repressive complex 2 (PRC2) and PRC2 trimethylation of histone 3 lysine 27 (H3K27me3) in the regulation of homeobox (HOX) (Marcinkiewicz and Gudas, 2013, Exp Cell Res) gene transcript levels in human oral keratinocytes (OKF6-TERT1R) and tongue squamous cell carcinoma (SCC) cells. Here, we assessed both the levels of various histone modifications at a subset of homeobox genes and genome wide DNA methylation patterns in OKF6-TERT1R and SCC-9 cells by using ERRBS (enhanced reduced representation bisulfite sequencing). We detected the H3K9me3 mark at HOXB7, HOXC10, HOXC13, and HOXD8 at levels higher in OKF6-TERT1R than in SCC-9 cells; at IRX1 and SIX2 the H3K9me3 levels were conversely higher in SCC-9 than in OKF6-TERT1R. The H3K79me3 mark was detectable only at IRX1 in OKF6-TERT1R and at IRX4 in SCC-9 cells. The levels of H3K4me3 and H3K36me3 marks correlate with the transcript levels of the assessed homeobox genes in both OKF6-TERT1R and SCC-9. We detected generally lower CpG methylation levels on DNA in SCC-9 cells at annotated genomic regions which were differentially methylated between OKF6-TERT1R and SCC-9 cells; however, some genomic regions, including the HOX gene clusters, showed DNA methylation at higher levels in SCC-9 than OKF6-TERT1R. Thus, both altered histone modification patterns and changes in DNA methylation are associated with dysregulation of homeobox gene expression in human oral cavity SCC cells, and this dysregulation potentially plays a role in the neoplastic phenotype of oral keratinocytes.Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Oral Cancer
Marcinkiewicz KM, Gudas LJAltered epigenetic regulation of homeobox genes in human oral squamous cell carcinoma cells.
Exp Cell Res. 2014; 320(1):128-43 [PubMed
] Article available free on PMC
after 01/01/2015 Related Publications
To gain insight into oral squamous cell carcinogenesis, we performed deep sequencing (RNAseq) of non-tumorigenic human OKF6-TERT1R and tumorigenic SCC-9 cells. Numerous homeobox genes are differentially expressed between OKF6-TERT1R and SCC-9 cells. Data from Oncomine, a cancer microarray database, also show that homeobox (HOX) genes are dysregulated in oral SCC patients. The activity of Polycomb repressive complexes (PRC), which causes epigenetic modifications, and retinoic acid (RA) signaling can control HOX gene transcription. HOXB7, HOXC10, HOXC13, and HOXD8 transcripts are higher in SCC-9 than in OKF6-TERT1R cells; using ChIP (chromatin immunoprecipitation) we detected PRC2 protein SUZ12 and the epigenetic H3K27me3 mark on histone H3 at these genes in OKF6-TERT1R, but not in SCC-9 cells. In contrast, IRX1, IRX4, SIX2 and TSHZ3 transcripts are lower in SCC-9 than in OKF6-TERT1R cells. We detected SUZ12 and the H3K27me3 mark at these genes in SCC-9, but not in OKF6-TERT1R cells. SUZ12 depletion increased HOXB7, HOXC10, HOXC13, and HOXD8 transcript levels and decreased the proliferation of OKF6-TERT1R cells. Transcriptional responses to RA are attenuated in SCC-9 versus OKF6-TERT1R cells. SUZ12 and H3K27me3 levels were not altered by RA at these HOX genes in SCC-9 and OKF6-TERT1R cells. We conclude that altered activity of PRC2 is associated with dysregulation of homeobox gene expression in human SCC cells, and that this dysregulation potentially plays a role in the neoplastic transformation of oral keratinocytes.Related: Oral Cancer
Ansari KI, Hussain I, Kasiri S, Mandal SSHOXC10 is overexpressed in breast cancer and transcriptionally regulated by estrogen via involvement of histone methylases MLL3 and MLL4.
J Mol Endocrinol. 2012; 48(1):61-75 [PubMed
] Related Publications
HOXC10 is a critical player in the development of spinal cord, formation of neurons, and associated with human leukemia. We found that HOXC10 is overexpressed in breast cancer and transcriptionally regulated by estrogen (17β-estradiol, E(2)). The HOXC10 promoter contains several estrogen response elements (ERE1-7, half-sites). A luciferase-based reporter assay showed that ERE1 and ERE6 of HOXC10 promoter are E(2) responsive. ERα and ERβ play critical roles in E(2)-mediated activation of HOXC10. Knockdown of ERα and ERβ downregulated E(2)-induced HOXC10 expression. ERα and ERβ bind to ERE1 and ERE6 regions in an E(2)-dependent manner. Additionally, knockdown of histone methylases MLL3 and MLL4 (but not MLL1 and MLL2) diminished E(2)-induced expression of HOXC10. MLL3 and MLL4 were bound to the ERE1 and ERE6 regions of HOXC10 promoter in an E(2)-dependent manner. Overall, we demonstrated that HOXC10 is overexpressed in breast cancer, and it is an E(2)-responsive gene. Histone methylases MLL3 and MLL4, along with ERs, regulate HOXC10 gene expression in the presence of E(2).Related: Breast Cancer MLL3 gene
Falaschi A, Abdurashidova G, Biamonti GDNA replication, development and cancer: a homeotic connection?
Crit Rev Biochem Mol Biol. 2010; 45(1):14-22 [PubMed
] Related Publications
The homeotic proteins are transcription factors, highly conserved in metazoan organisms, exerting a pivotal role in development and differentiation. They individually display a loose specificity for the DNA sequence they can bind, but operate mainly in multi-molecular associations that assure their target and function specificity. Homeotic proteins are known to play a role in the positive or negative regulation of cell proliferation. Furthermore, many homeotic proteins are actually proto-oncogenes, since different translocations involving their genes cause tumors, particularly in the hematopoietic system. A one-hybrid screen to detect proteins with affinity for the lamin B2 replication origin identified three homeotic proteins, namely HoxA13, HoxC10 and HoxC13. Recent data demonstrate that the HoxC13 oncoprotein specifically associates with replication foci and binds in vitro and in vivo to several human DNA replication origins. Moreover, Hox proteins interact with geminin, a regulator of cell cycle progression, and control the interaction of this protein with the DNA replication licensing factor Ctd1. Thus, the homeotic proteins, by participating directly in the function of DNA replication origins, may provide a direct link between the accurate regulation of DNA replication required by the morphogenetic program and the deregulation of this process typical of cancer.Related: Cancer Prevention and Risk Reduction
Zhai Y, Kuick R, Nan B, et al.Gene expression analysis of preinvasive and invasive cervical squamous cell carcinomas identifies HOXC10 as a key mediator of invasion.
Cancer Res. 2007; 67(21):10163-72 [PubMed
] Related Publications
If left untreated, a subset of high-grade squamous intraepithelial lesions (HSIL) of the cervix will progress to invasive squamous cell carcinomas (SCC). To identify genes whose differential expression is linked to cervical cancer progression, we compared gene expression in microdissected squamous epithelial samples from 10 normal cervices, 7 HSILs, and 21 SCCs using high-density oligonucleotide microarrays. We identified 171 distinct genes at least 1.5-fold up-regulated (and P < 0.001) in the SCCs relative to HSILs and normal cervix samples. Differential expression of a subset of these genes was confirmed by quantitative reverse transcription-PCR and immunohistochemical staining of cervical tissue samples. One of the genes up-regulated during progression, HOXC10, was selected for functional studies aimed at assessing its role in mediating invasive behavior of neoplastic squamous epithelial cells. Elevated HOXC10 expression was associated with increased invasiveness of human papillomavirus-immortalized keratinocytes and cervical cancer-derived cell lines in both in vitro and in vivo assays. Cervical cancer cells with high endogenous levels of HOXC10 were less invasive after short hairpin RNA-mediated knockdown of HOXC10 expression. Our findings support a key role for the HOXC10 homeobox protein in cervical cancer progression. Other genes with differential expression in invasive SCC versus HSIL may contribute to tumor progression or may be useful as markers for cancer diagnosis or progression risk.Related: Cervical Cancer
Abba MC, Sun H, Hawkins KA, et al.Breast cancer molecular signatures as determined by SAGE: correlation with lymph node status.
Mol Cancer Res. 2007; 5(9):881-90 [PubMed
] Article available free on PMC
after 01/01/2015 Related Publications
Global gene expression measured by DNA microarray platforms have been extensively used to classify breast carcinomas correlating with clinical characteristics, including outcome. We generated a breast cancer Serial Analysis of Gene Expression (SAGE) high-resolution database of approximately 2.7 million tags to perform unsupervised statistical analyses to obtain the molecular classification of breast-invasive ductal carcinomas in correlation with clinicopathologic features. Unsupervised statistical analysis by means of a random forest approach identified two main clusters of breast carcinomas, which differed in their lymph node status (P=0.01); this suggested that lymph node status leads to globally distinct expression profiles. A total of 245 (55 up-modulated and 190 down-modulated) transcripts were differentially expressed between lymph node (+) and lymph node (-) primary breast tumors (fold change, >or=2; P<0.05). Various lymph node (+) up-modulated transcripts were validated in independent sets of human breast tumors by means of real-time reverse transcription-PCR (RT-PCR). We validated significant overexpression of transcripts for HOXC10 (P=0.001), TPD52L1 (P=0.007), ZFP36L1 (P=0.011), PLINP1 (P=0.013), DCTN3 (P=0.025), DEK (P=0.031), and CSNK1D (P=0.04) in lymph node (+) breast carcinomas. Moreover, the DCTN3 (P=0.022) and RHBDD2 (P=0.002) transcripts were confirmed to be overexpressed in tumors that recurred within 6 years of follow-up by real-time RT-PCR. In addition, meta-analysis was used to compare SAGE data associated with lymph node (+) status with publicly available breast cancer DNA microarray data sets. We have generated evidence indicating that the pattern of gene expression in primary breast cancers at the time of surgical removal could discriminate those tumors with lymph node metastatic involvement using SAGE to identify specific transcripts that behave as predictors of recurrence as well.Related: Breast Cancer
Rahmatpanah FB, Carstens S, Guo J, et al.Differential DNA methylation patterns of small B-cell lymphoma subclasses with different clinical behavior.
Leukemia. 2006; 20(10):1855-62 [PubMed
] Related Publications
Non-Hodgkin's lymphoma (NHL) is a group of malignancies of the immune system with variable clinical behaviors and diverse molecular features. Despite the progress made in classification of NHLs based on classical methods, molecular classifications are a work in progress. Toward this goal, we used an array-based technique called differential methylation hybridization (DMH) to study small B-cell lymphoma (SBCL) subtypes. A total of 43 genomic DMH experiments were performed. From these results, several statistical methods were used to generate a set of differentially methylated genes for further validation. Methylation of LHX2, POU3F3, HOXC10, NRP2, PRKCE, RAMP, MLLT2, NKX6.1, LRP1B and ARF4 was validated in cell lines and patient samples and demonstrated subtype-related preferential methylation patterns. For LHX2 and LRP1B, bisulfite sequencing, real-time reverse transcriptase-polymerase chain reaction and induction of gene expression following treatment with the demethylating agent, 5'-aza-2'-deoxycytidine, were confirmed. This new epigenetic information is helping to define molecular portraits of distinct subtypes of SBCL that are not recognized by current classification systems and provides valuable potential insights into the biology of these tumors.Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology LRP1B
López R, Garrido E, Vázquez G, et al.A subgroup of HOX Abd-B gene is differentially expressed in cervical cancer.
Int J Gynecol Cancer. 2006 May-Jun; 16(3):1289-96 [PubMed
] Related Publications
The HOX genes are a family of transcription factors that bind to specific sequences of DNA in target genes regulating their expression. The role of HOX genes in adult cell differentiation is still obscure, but growing evidence suggests that they may play an important role in the development of cancer. In order to study the role of the HOX Abd-B genes in cervical cancer, we analyzed their expression in cervical tissues. Reverse transcription-polymerase chain reaction and RNA in situ hybridization were used to detect HOX Abd-B messenger RNA expression in nine normal cervical tissues and ten cervical carcinomas. The normal tissues were human papillomavirus (HPV) negative, whereas all invasive carcinomas included were HPV16 positive. In this study, we show that HOXA9, A10, A11, A13, B9, D11, and D13 genes are expressed in both the epithelium of normal tissues and neoplastic cells from squamous cervical carcinomas. Interestingly, the HOXC10 and D12 genes were not expressed in any cervical tissues; however, HOXB13, C9, C11, C12, C13, D9, and D10 genes were expressed only in the tumoral tissues but not in the normal cervix. Our findings suggest that the expression of HOXB13, D9, D10, and HOXC cluster (HOXC9, C11-C13) genes might be an important step involved in cervical cancer.Related: Cervical Cancer
Rozovskaia T, Feinstein E, Mor O, et al.Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4 : 11) abnormality.
Oncogene. 2001; 20(7):874-8 [PubMed
] Related Publications
Rearrangements of the human ALL-1 gene are frequently encountered in acute lymphocytic leukemias (ALL) and acute myeloid leukemias (AML). These rearrangements are mostly due to chromosome translocations and result in production of chimeric proteins composed of the N-terminal fragment of ALL-1 and the C-terminal segments of the partner proteins. The most common chromosome translocation involving ALL-1 is the t(4 : 11) associated with ALL. ALL-1 is the human homologue of Drosophila trithorax and directly activates transcription of multiple Hox genes. A preliminary DNA microarray screen indicated that the Meis1, HoxA9 and AC133 genes were overexpressed in ALLs with t(4 : 11), compared to ALLs with very similar phenotype but without the chromosomal abnormality. These genes, as well as additional five Hox genes, were subjected to comprehensive semi-quantitative or quantitative RT-PCR analysis in 57 primary ALL and AML tumors. Meis1 and HoxA9 were found expressed in 13/14 of ALLs with the t(4 : 11) and in 8/8 of AMLs with ALL-1 rearrangements. The two genes were not consistently transcribed in other types of ALL. AC133 was transcribed in 13/14 of ALLs with t(4 : 11), but in only 4/8 of AMLs with ALL-1 rearrangements. HoxA10 was expressed in most leukemias with ALL-1 alterations, but was also transcribed in PrePreB CD10(-) ALLs lacking the t(4 : 11). Expression of HoxA5, HoxA7, HoxC8 and HoxC10 did not correlate with ALL-1 rearrangements. Coexpression of Meis1 and HoxA9, overexpression of HoxA10, and overexpression or fusion of HoxA9 were previously implicated in certain acute myeloid leukemias in mice and humans. The present work suggests that upregulation of Meis1, HoxA9, and possibly HoxA10 might also play a role in pathogenesis of acute lymphocytic and acute myeloid leukemias associated with ALL-1 fusions.Related: Chromosome 11 Chromosome 4 Acute Lymphocytic Leukemia (ALL) MLL gene HOXA9 gene