Gene Summary

Gene:HOXC13; homeobox C13
Aliases: HOX3, ECTD9, HOX3G
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 product of this gene may play a role in the development of hair, nail, and filiform papilla. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:homeobox protein Hox-C13
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: HOXC13 (cancer-related)

Tatangelo F, Di Mauro A, Scognamiglio G, et al.
Posterior HOX genes and HOTAIR expression in the proximal and distal colon cancer pathogenesis.
J Transl Med. 2018; 16(1):350 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Increasing evidences showed that the location of the primary tumor on the right (proximal) or left (distal) side of the colon have a prognostic/predictive value for colon cancer patients. However, the understanding of the molecular mechanisms that contribute to the pathogenesis in different location of colon is still unclear. Probably an important role could be played by genes that control the spatial-temporal development of bodily structures, such as HOX genes.
METHODS: The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes and of the HOX regulating lncRNA HOTAIR in distal and proximal CRC cases. We have carried out a Tissue Micro Array with left and right CRC samples associated with all clinical-pathological parameters of patients. The expression of HOX genes was evaluated by immunohistochemistry and the staining of HOTAIR was performed by in situ hybridization using a specifically designed LNA probe.
RESULTS: All paralogous 13 HOX genes and HOTAIR are silent in normal tissue and expressed in CRC samples. HOXB13, HOXC13 and HOTAIR showed a statistical association with lymph nodes metastasis (p value = 0.003, p value = 0.05, p value = 0.04). HOXB13, HOXC13 and lncRNA HOTAIR are overexpressed in right CRCs samples (p value < 0 and p value = 0.021). HOTAIR is also strongly correlated with HOXB13 (p value = 0.02) and HOXC13 (p value = 0.042) expression.
CONCLUSIONS: Our data highlighted an important role of posterior HOX genes in colorectal cancer carcinogenesis. Specifically, the aberrant expression of the HOXB13, HOXC13 and HOTAIR in proximal colon cancers could add an important dowel in understanding molecular mechanisms related to tumor pathogenesis in this location.

Luo J, Wang Z, Huang J, et al.
HOXC13 promotes proliferation of esophageal squamous cell carcinoma via repressing transcription of CASP3.
Cancer Sci. 2018; 109(2):317-329 [PubMed] Free Access to Full Article Related Publications
Esophageal squamous cell carcinoma (ESCC), the dominant subtype of esophageal cancer, is one of the most common digestive tumors worldwide. In this study, we confirmed that HOXC13, a member of the homeobox HOXC gene family, was significantly upregulated in ESCC and its overexpression was associated with poorer clinical characteristics and worse prognosis. Moreover, knockdown of HOXC13 inhibited proliferation and induced apoptosis of ESCC through upregulating CASP3. ChIP analysis revealed that HOXC13 repressed transcription of CASP3 through directly targeting the promotor region of CASP3. We also found that miR-503 downregulated HOXC13, by directly targeting its 3'UTR, and inhibited proliferation of ESCC. In conclusion, our study demonstrates that HOXC13, which is directly targeted by miR-503, promotes proliferation and inhibits apoptosis of ESCC through repressing transcription of CASP3.

Luan L, Shi J, Yu Z, Andl T
The major miR-31 target genes STK40 and LATS2 and their implications in the regulation of keratinocyte growth and hair differentiation.
Exp Dermatol. 2017; 26(6):497-504 [PubMed] Related Publications
Emerging evidence indicates that even subtle changes in the expression of key genes of signalling pathways can have profound effects. MicroRNAs (miRNAs) are masters of subtlety and generally have only mild effects on their target genes. The microRNA miR-31 is one of the major microRNAs in many cutaneous conditions associated with activated keratinocytes, such as the hyperproliferative diseases psoriasis, non-melanoma skin cancer and hair follicle growth. miR-31 is a marker of the hair growth phase, and in our miR-31 transgenic mouse model it impairs the function of keratinocytes. This leads to aberrant proliferation, apoptosis, and differentiation that results in altered hair growth, while the loss of miR-31 leads to increased hair growth. Through in vitro and in vivo studies, we have defined a set of conserved miR-31 target genes, including LATS2 and STK40, which serve as new players in the regulation of keratinocyte growth and hair follicle biology. LATS2 can regulate growth of keratinocytes and we have identified a function of STK40 that can promote the expression of key hair follicle programme regulators such as HR, DLX3 and HOXC13.

Komisarof J, McCall M, Newman L, et al.
A four gene signature predictive of recurrent prostate cancer.
Oncotarget. 2017; 8(2):3430-3440 [PubMed] Free Access to Full Article Related Publications
Prostate cancer is the most common form of non-dermatological cancer among US men, with an increasing incidence due to the aging population. Patients diagnosed with clinically localized disease identified as intermediate or high-risk are often treated by radical prostatectomy. Approximately 33% of these patients will suffer recurrence after surgery. Identifying patients likely to experience recurrence after radical prostatectomy would lead to improved clinical outcomes, as these patients could receive adjuvant radiotherapy. Here, we report a new tool for prediction of prostate cancer recurrence based on the expression pattern of a small set of cooperation response genes (CRGs). CRGs are a group of genes downstream of cooperating oncogenic mutations previously identified in a colon cancer model that are critical to the cancer phenotype. We show that systemic dysregulation of CRGs is also found in prostate cancer, including a 4-gene signature (HBEGF, HOXC13, IGFBP2, and SATB1) capable of differentiating recurrent from non-recurrent prostate cancer. To develop a suitable diagnostic tool to predict disease outcomes in individual patients, multiple algorithms and data handling strategies were evaluated on a training set using leave-one-out cross-validation (LOOCV). The best-performing algorithm, when used in combination with a predictive nomogram based on clinical staging, predicted recurrent and non-recurrent disease outcomes in a blinded validation set with 83% accuracy, outperforming previous methods. Disease-free survival times between the cohort of prostate cancers predicted to recur and predicted not to recur differed significantly (p = 1.38x10-6). Therefore, this test allows us to accurately identify prostate cancer patients likely to experience future recurrent disease immediately following removal of the primary tumor.

Hiraki M, Maeda T, Bouillez A, et al.
MUC1-C activates BMI1 in human cancer cells.
Oncogene. 2017; 36(20):2791-2801 [PubMed] Free Access to Full Article Related Publications
B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is a component of the polycomb repressive complex 1 (PRC1) complex that is overexpressed in breast and other cancers, and promotes self-renewal of cancer stem-like cells. The oncogenic mucin 1 (MUC1) C-terminal (MUC1-C) subunit is similarly overexpressed in human carcinoma cells and has been linked to their self-renewal. There is no known relationship between MUC1-C and BMI1 in cancer. The present studies demonstrate that MUC1-C drives BMI1 transcription by a MYC-dependent mechanism in breast and other cancer cells. In addition, we show that MUC1-C blocks miR-200c-mediated downregulation of BMI1 expression. The functional significance of this MUC1-C→︀BMI1 pathway is supported by the demonstration that targeting MUC1-C suppresses BMI1-induced ubiquitylation of H2A and thereby derepresses homeobox HOXC5 and HOXC13 gene expression. Notably, our results further show that MUC1-C binds directly to BMI1 and promotes occupancy of BMI1 on the CDKN2A promoter. In concert with BMI1-induced repression of the p16

Yu M, Al-Dallal S, Al-Haj L, et al.
Transcriptional regulation of the proto-oncogene Zfp521 by SPI1 (PU.1) and HOXC13.
Genesis. 2016; 54(10):519-533 [PubMed] Free Access to Full Article Related Publications
The mouse zinc-finger gene Zfp521 (also known as ecotropic viral insertion site 3; Evi3; and ZNF521 in humans) has been identified as a B-cell proto-oncogene, causing leukemia in mice following retroviral insertions in its promoter region that drive Zfp521 over-expression. Furthermore, ZNF521 is expressed in human hematopoietic cells, and translocations between ZNF521 and PAX5 are associated with pediatric acute lymphoblastic leukemia. However, the regulatory factors that control Zfp521 expression directly have not been characterized. Here we demonstrate that the transcription factors SPI1 (PU.1) and HOXC13 synergistically regulate Zfp521 expression, and identify the regions of the Zfp521 promoter required for this transcriptional activity. We also show that SPI1 and HOXC13 activate Zfp521 in a dose-dependent manner. Our data support a role for this regulatory mechanism in vivo, as transgenic mice over-expressing Hoxc13 in the fetal liver show a strong correlation between Hoxc13 expression levels and Zfp521 expression. Overall these experiments provide insights into the regulation of Zfp521 expression in a nononcogenic context. The identification of transcription factors capable of activating Zfp521 provides a foundation for further investigation of the regulatory mechanisms involved in ZFP521-driven cell differentiation processes and diseases linked to Zfp521 mis-expression.

Mehrian-Shai R, Yalon M, Moshe I, et al.
Identification of genomic aberrations in hemangioblastoma by droplet digital PCR and SNP microarray highlights novel candidate genes and pathways for pathogenesis.
BMC Genomics. 2016; 17:56 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The genetic mechanisms underlying hemangioblastoma development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays and droplet digital PCR analysis to detect copy number variations (CNVs) in total of 45 hemangioblastoma tumors.
RESULTS: We identified 94 CNVs with a median of 18 CNVs per sample. The most frequently gained regions were on chromosomes 1 (p36.32) and 7 (p11.2). These regions contain the EGFR and PRDM16 genes. Recurrent losses were located at chromosome 12 (q24.13), which includes the gene PTPN11.
CONCLUSIONS: Our findings provide the first high-resolution genome-wide view of chromosomal changes in hemangioblastoma and identify 23 candidate genes: EGFR, PRDM16, PTPN11, HOXD11, HOXD13, FLT3, PTCH, FGFR1, FOXP1, GPC3, HOXC13, HOXC11, MKL1, CHEK2, IRF4, GPHN, IKZF1, RB1, HOXA9, and micro RNA, such as hsa-mir-196a-2 for hemangioblastoma pathogenesis. Furthermore, our data implicate that cell proliferation and angiogenesis promoting pathways may be involved in the molecular pathogenesis of hemangioblastoma.

Battistella M, Carlson JA, Osio A, et al.
Skin tumors with matrical differentiation: lessons from hair keratins, beta-catenin and PHLDA-1 expression.
J Cutan Pathol. 2014; 41(5):427-36 [PubMed] Related Publications
BACKGROUND: Pilomatricomas are tumors that emulate the differentiation of matrix cells of the hair follicle, showing cortical differentiation, with sequential expression of K35 and K31 keratins. Beta-catenin gene is frequently mutated in pilomatricoma, leading to beta-catenin nuclear accumulation, and to downstream expression of LEF1. Skin matrical tumors other than pilomatricoma are very rare, and comprise purely matrical tumors and focally matrical tumors. We aimed at studying cortical differentiation, beta-catenin pathway and expression of the follicular stem-cell marker PHLDA1 in a series of matrical tumors other than pilomatricoma.
METHODS: In 36 prospectively collected tumors, K31, K35, CK17, LEF1, HOXC13, beta-catenin and PHLDA1 expressions were evaluated. Five pilomatricomas were used as controls.
RESULTS: In 18 purely matrical tumors (11 matrical carcinomas, 4 melanocytic matricomas, 3 matricomas) and 18 focally matrical tumors (11 basal cell carcinomas, 3 trichoepithelioma/trichoblastomas, 4 others), sequential K35, HOXC13 and K31 expressions were found, indicating cortical differentiation. Germinative matrix cells were always CK17-, and showed nuclear beta-catenin accumulation, with LEF1 and PHLDA1 expressions.
CONCLUSIONS: Nuclear beta-catenin and LEF1 expression was highly conserved in matrical tumors, and suggested a common tumorigenesis driven by Wnt pathway activation. PHLDA1 was consistently expressed in matrical tumors and in areas of matrical differentiation.

Marcinkiewicz KM, Gudas LJ
Altered histone mark deposition and DNA methylation at homeobox genes in human oral squamous cell carcinoma.
J Cell Physiol. 2014; 229(10):1405-16 [PubMed] Free Access to Full Article Related Publications
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.

Cantile M, Galletta F, Franco R, et al.
Hyperexpression of HOXC13, located in the 12q13 chromosomal region, in well‑differentiated and dedifferentiated human liposarcomas.
Oncol Rep. 2013; 30(6):2579-86 [PubMed] Free Access to Full Article Related Publications
Liposarcoma (LPS) is the most common soft tissue neoplasm in adults and is characterized by neoplastic adipocyte proliferation. Some subtypes of LPSs show aberrations involving the chromosome 12. The most frequent are t(12;16) (q13;p11) present in more than 90% of myxoid LPSs and 12q13-15 amplification in well-differentiated and dedifferentiated LPSs. In this region, there are important oncogenes such as CHOP (DDIT3), GLI, MDM2, CDK4, SAS, HMGA2, but also the HOXC locus, involved in development and tumor progression. In this study, we evaluated the expression of HOXC13, included in this chromosomal region, in a series of adipocytic tumors. We included 18 well-differentiated, 4 dedifferentiated, 11 myxoid and 6 pleomorphic LPSs as well as 13 lipomas in a tissue microarray. We evaluated the HOXC13 protein and gene expression by immunohistochemistry and quantitative PCR. Amplification/translocation of the 12q13-15 region was verified by FISH. Immunohistochemical HOXC13 overexpression was observed in all well-differentiated and dedifferentiated LPSs, all characterized by the chromosome 12q13-15 amplification, and confirmed by quantitative PCR analysis. In conclusion, our data show a deregulation of the HOXC13 marker in well‑differentiated and dedifferentiated LPSs, possibly related to 12q13-15 chromosomal amplification.

Marcinkiewicz KM, Gudas LJ
Altered epigenetic regulation of homeobox genes in human oral squamous cell carcinoma cells.
Exp Cell Res. 2014; 320(1):128-43 [PubMed] Free Access to Full Article 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.

Cantile M, Scognamiglio G, Anniciello A, et al.
Increased HOX C13 expression in metastatic melanoma progression.
J Transl Med. 2012; 10:91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The process of malignant transformation, progression and metastasis of melanoma is not completely understood. Recently, the microarray technology has been used to survey transcriptional differences that might provide insight into the metastatic process, but the validation of changing gene expression during metastatic transition period is poorly investigated. A large body of literature has been produced on the role of the HOX genes network in tumour evolution, suggesting the involvement of HOX genes in several types of human cancers. Deregulated paralogous group 13 HOX genes expression has been detected in melanoma, cervical cancer and odonthogenic tumors. Among these, Hox C13 is also involved in the expression control of the human keratin genes hHa5 and hHa2, and recently it was identified as a member of human DNA replication complexes.
METHODS: In this study, to investigate HOX C13 expression in melanoma progression, we have compared its expression pattern between naevi, primary melanoma and metastasis. In addition HOXC13 profile pattern of expression has been evaluated in melanoma cell lines.
RESULTS: Our results show the strong and progressive HOX C13 overexpression in metastatic melanoma tissues and cytological samples compared to nevi and primary melanoma tissues and cells.
CONCLUSIONS: The data presentated in the paper suggest a possible role of HOX C13 in metastatic melanoma switch.

Chen F, Li Y, Wang L, Hu L
Knockdown of BMI-1 causes cell-cycle arrest and derepresses p16INK4a, HOXA9 and HOXC13 mRNA expression in HeLa cells.
Med Oncol. 2011; 28(4):1201-9 [PubMed] Related Publications
The human oncogene B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is a member of the mammalian Polycomb group family. The overexpression of BMI-1 is associated with human malignancies. In this study, the effects of knockdown of BMI-1 by shRNA-mediated RNA interference on cell cycle and possible downstream targets in human cervical adenocarcinoma HeLa cells were investigated. As a result, when the shRNA plasmid was stably introduced into the cell line, the mRNA and protein of BMI-1 were specifically down-regulated, and the cells increased in the phase of G1 and cells in S phase significantly decreased by flow cytometric analysis; the knockdown of BMI-1 expression could lead to significant up-regulation of p16INK4a, HOXA9 and HOXC13 mRNA expression, but hTERT and HOXB4 mRNA expression did not change significantly. In conclusion, RNAi-mediated knockdown of BMI-1 expression can induce cell-cycle arrest and up-regulate p16INK4a, HOXA9 and HOXC13 in HeLa cells. Our results suggest that targeting BMI-1 might be a therapeutic potential for the treatment of cancer.

Falaschi A, Abdurashidova G, Biamonti G
DNA 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.

La Starza R, Brandimarte L, Pierini V, et al.
A NUP98-positive acute myeloid leukemia with a t(11;12)(p15;q13) without HOXC cluster gene involvement.
Cancer Genet Cytogenet. 2009; 193(2):109-11 [PubMed] Related Publications
We report a case of adult acute myeloid leukemia with a new t(11;12)(p15;q13) underlying a NUP98 rearrangement without HOXC cluster gene involvement. We designed a specific double-color double-fusion FISH assay to discriminate between this t(11;12)(p15;q13) and those producing NUP98-HOXC11 or NUP98-HOXC13. Our fluorescence in situ hybridization (FISH) showed that putative candidate partners mapping 600 kilobases centromeric to HOXC were RARG (retinoic acid receptor gamma), MFSD5 (major facilitator superfamily domain containing 5), and ESPL1 (extra spindle pole bodies homolog 1). It is noteworthy that so far only ESPL1 has been implicated in human cancers. This FISH assay is useful for diagnostic screening of NUP98-positive leukemias.

Tosić N, Stojiljković M, Colović N, et al.
Acute myeloid leukemia with NUP98-HOXC13 fusion and FLT3 internal tandem duplication mutation: case report and literature review.
Cancer Genet Cytogenet. 2009; 193(2):98-103 [PubMed] Related Publications
The NUP98 gene at chromosome band 11p15 is known to be fused to a number of different partners in various hematological malignancies. The most frequently observed fusion partners of NUP98 are the homeobox family of transcriptional factors (HOX genes). We report a case of de novo AML M4 subtype, with a t(11;12)(p15;q13) translocation, generating a NUP98-HOXC13 chimeric transcript. Molecular analysis showed that the exon 16 of NUP98 was fused in frame with exon 2 of HOXC13. The patient was also positive for FLT3 internal tandem duplication (ITD), another molecular marker for the disease. Comparative study of data on the fusion of HOXC cluster and NUP98 gene revealed that it is a rare event, found exclusively in AML patients. To our knowledge, this is the first case of t(11;12)(p15;q13) in de novo AML-M4 in association with FLT3 ITD mutation. Coexistence of NUP98-HOXC13 fusion and FLT3 ITD mutation is likely relevant in the process of leukemogenesis.

Yamada T, Shimizu T, Suzuki M, et al.
Interaction between the homeodomain protein HOXC13 and ETS family transcription factor PU.1 and its implication in the differentiation of murine erythroleukemia cells.
Exp Cell Res. 2008; 314(4):847-58 [PubMed] Related Publications
Some of homeodomain proteins and the ETS family of transcription factors are involved in hematopoiesis. RT-PCR analysis revealed that the HOXC13 and PU.1 genes were expressed in murine erythroleukemia (MEL) cells and their levels decreased during DMSO-induced differentiation into erythroid cells. HOXC13 bound to the ETS domain of PU.1 through a region encompassing the C-terminal part of the homeodomain and the most C-terminal region and enhanced the transcriptional activity of PU.1. Enforced expression of HOXC13 in MEL cells resulted in the suppression of beta-globin gene expression. In MEL cells overexpressing HOXC13 and PU.1, which also inhibits the differentiation of MEL cells, no synergistic effect on the suppression of beta-globin gene expression was observed. However, in the presence of DMSO, the expression levels of the beta-globin gene in the cells overexpressing HOXC13 and PU.1 were, unexpectedly, higher than those in the cells overexpressing PU.1 alone. The levels of PU.1 protein were markedly decreased despite that the levels of mRNA were preserved in the cells overexpressing PU.1 and HOXC13. It was, thus, suggested that although HOXC13 negatively regulates the differentiation of MEL cells into erythroid cells, it antagonizes PU.1 possibly by down-regulation of PU.1 protein in the presence of a differentiation stimulus.

Yamashita T, Tazawa S, Yawei Z, et al.
Suppression of invasive characteristics by antisense introduction of overexpressed HOX genes in ovarian cancer cells.
Int J Oncol. 2006; 28(4):931-8 [PubMed] Related Publications
HOX genes encode transcription factors that function to establish basic body pattern during embryogenesis and maintain the function of specific organs in the adult. Recent studies have demonstrated that HOX genes are also involved in oncogenesis in a range of malignancies. To elucidate whether HOX genes contribute to ovarian carcinogenesis, we created an expression profile of HOX genes using ovarian derived materials from surgical samples and epithelial ovarian cancer cells derived from five different cell lines. Real-time quantitative RT-PCR assay indicated overexpression of 14 HOX genes in clusters A and B but only 2 genes in clusters C and D. Of the 16 HOX genes, overexpression of paralogs of HOX3, HOX4 and HOX7 is seen in cluster A and B, and of HOX13 in all paralogs. In addition, HOXB7, HOXA13 and HOXB13 showed high levels of overexpression in cancer cells and tissues whereas no or little expression was observed in normal controls. To examine whether overexpressed HOX genes regulate invasion of ovarian cancer cells directly, we introduced an antisense DNA fragment of overexpressed HOXB7 and HOXB13, and HOXC5 that did not show overexpression into SKOV3 cells by electroporation. Antisense introduction followed by chemoinvasion assay using matrigel chamber demonstrated that SKOV3 cells introduced an antisense of each HOXB7 and HOXB13 showed 85% and 50% reduction of invasion ability compared to the parental SKOV3 cells, respectively. In contrast, antisense of HOXC5 introduced cells showed no significant difference of the invasion ability. These results suggest an important role of overexpressed HOX genes, especially for invasive characteristics of ovarian cancer cells.

Pineault N, Abramovich C, Humphries RK
Transplantable cell lines generated with NUP98-Hox fusion genes undergo leukemic progression by Meis1 independent of its binding to DNA.
Leukemia. 2005; 19(4):636-43 [PubMed] Related Publications
Hox genes have been identified in chromosomal translocations involving the nucleoporin gene NUP98. Though the resulting chimeric proteins directly participate in the development of leukemia, the long latency and monoclonal nature of the disease support the requirement for secondary mutation(s), such as those leading to overexpression of Meis1. Models to identify such events and to study leukemic progression are rare and labor intensive. Herein, we took advantage of the strong transforming potential of NUP98-HOXD13 or NUP98-HOXA10 to establish preleukemic myeloid lines from bone marrow cells that faithfully replicate the first step of Hox-induced leukemogenesis. These lines contain early granulomonocytic progenitors with extensive in vitro self-renewal capacity, short-term myeloid repopulating activity and low propensity for spontaneous leukemic conversion. We exploit such lines to show that Meis1 efficiently induces their leukemic progression and demonstrate a high frequency of preleukemic cells in the cultures. Furthermore, we document that the leukemogenic potential of Meis1 is independent of its direct binding to DNA and likely reflects its ability to increase the repopulating capacity of the preleukemic cells by increasing their self-renewal/proliferative capacity. The availability of lines with repopulating potential and capacity for leukemic conversion should open new avenues for understanding progression of Hox-mediated acute myeloid leukemia.

Kobzev YN, Martinez-Climent J, Lee S, et al.
Analysis of translocations that involve the NUP98 gene in patients with 11p15 chromosomal rearrangements.
Genes Chromosomes Cancer. 2004; 41(4):339-52 [PubMed] Related Publications
The NUP98 gene has been reported to be fused with at least 15 partner genes in leukemias with 11p15 translocations. We report the results of screening of cases with cytogenetically documented rearrangements of 11p15 and the subsequent identification of involvement of NUP98 and its partner genes. We identified 49 samples from 46 hematology patients with 11p15 (including a few with 11p14) abnormalities, and using fluorescence in situ hybridization (FISH), we found that NUP98 was disrupted in 7 cases. With the use of gene-specific FISH probes, in 6 cases, we identified the partner genes, which were PRRX1 (PMX1; in 2 cases), HOXD13, RAP1GDS1, HOXC13, and TOP1. In the 3 cases for which RNA was available, RT-PCR was performed, which confirmed the FISH results and identified the location of the breakpoints in patient cDNA. Our data confirm the previous findings that NUP98 is a recurrent target in various types of leukemia.

Cribier B, Peltre B, Grosshans E, et al.
On the regulation of hair keratin expression: lessons from studies in pilomatricomas.
J Invest Dermatol. 2004; 122(5):1078-83 [PubMed] Related Publications
Human hair follicles exhibit a complex pattern of sequential hair keratin expression in the hair matrix, cuticle, and cortex. In pilomatricomas, that is, benign skin tumors thought to arise from germinative matrix cells of the hair follicle and retaining morphological signs of cortical differentiation, this differential hair keratin pattern has been shown to be faithfully preserved in the lower and upper transitional cell compartments of the tumors. Here we show that also the co-expression of hair keratin hHa5 with its regulatory nuclear homeoprotein HOXC13 in matrix cells of the hair follicle is maintained in lower transitional cells of pilomatricomas. In contrast, the nuclear co-expression of LEF1 and beta-catenin, which in the hair follicle has been postulated to initiate cortex cell differentiation through the induction of hair keratin hHa1 expression (Merill et al, Genes Dev 15:1688-1705, 2001), is not preserved in upper transitional cells of pilomatricomas. Although these cells correctly express hHa1, they are completely devoid of LEF1 and nuclear LEF1/beta-catenin co-expression is shifted to a subpopulation of hair keratin-free basaloid cells of the tumors. These data imply that unlike the normal hair follicle, cortical differentiation in pilomatricomas is not under the control of the canonical Wnt signaling pathway.

La Starza R, Trubia M, Crescenzi B, et al.
Human homeobox gene HOXC13 is the partner of NUP98 in adult acute myeloid leukemia with t(11;12)(p15;q13).
Genes Chromosomes Cancer. 2003; 36(4):420-3 [PubMed] Related Publications
The chimeric gene NUP98/HOXC13 was detected in a patient with a de novo acute myeloid leukemia and a t(11;12)(p15;q13). Fluorescence in situ hybridization with PAC1173K1 identified the breakpoint on 11p15, indicating that the NUP98 gene was involved in the translocation. At 12q13, the breakpoint fell within BAC 578A18, selected for the homeobox C (HOXC) cluster genes. RACE-PCR showed that HOXC13 was the partner gene of NUP98. To date, HOXC13 is the eighth homeobox gene that, as the result of a reciprocal translocation, fuses with NUP98 in myeloid malignancies.

Panagopoulos I, Isaksson M, Billström R, et al.
Fusion of the NUP98 gene and the homeobox gene HOXC13 in acute myeloid leukemia with t(11;12)(p15;q13).
Genes Chromosomes Cancer. 2003; 36(1):107-12 [PubMed] Related Publications
The NUP98 gene at 11p15 is known to be fused to DDX10, HOXA9, HOXA11, HOXA13, HOXD11, HOXD13, LEDGF, NSD1, NSD3, PMX1, RAP1GDS1, and TOP1 in various hematologic malignancies. The common theme in all NUP98 chimeras is a transcript consisting of the 5' part of NUP98 and the 3' portion of the partner gene; however, apart from the frequent fusion to different homeobox genes, there is no apparent similarity among the other partners. We here report a de novo acute myeloid leukemia with a t(11;12)(p15;q13), resulting in a novel NUP98/HOXC13 fusion. Fluorescence in situ hybridization analyses, by the use of probes covering NUP98 and the HOXC gene cluster at 12q13, revealed a fusion signal at the der(11)t(11;12), indicating a NUP98/HOXC chimera, whereas no fusion was found on the der(12)t(11;12), suggesting that the translocation was accompanied by a deletion of the reciprocal fusion gene. Reverse transcription-PCR and sequence analyses showed that exon 16 (nucleotide 2290) of NUP98 was fused in-frame with exon 2 (nucleotide 852) of HOXC13. Neither the HOXC13/NUP98 transcript nor the normal HOXC13 was expressed. The present results, together with previous studies of NUP98/homeobox gene fusions, strongly indicate that NUP98/HOXC13 is of pathogenetic importance in t(11;12)-positive acute myeloid leukemia.

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