CHST11 (carbohydrate (chondroitin 4) sulfotransferase 11)

2014-04-01   Michael Klüppel 

Ann, Robert H. Lurie Childrens Hospital of Chicago Research Center, Chicago, IL, USA, Department of Pediatrics, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA




Atlas Image
Genomic organization of the CHST11 locus on chromosome 12q23.3, encompassing nucleotides 104850692 to 105155792. Orientation (5 to 3) of CHST11, and neighbouring genes TXNRD1, SCL41A2, and ALDH1L2 are indicated by arrowheads. cen: centromere; qter: telomere of q-arm. Adapted from USCS Genome Browser, hg19 (November 2013).


The CHST11 gene spans 305 kb on chromosome 12q23.3.


The CHST11 gene contains one 5 non-coding exon and three coding exons and is transcribed into a 5.7 kb mRNA. Transcription of CHST11 has been shown to be positively regulated by signaling through transforming growth factor-beta (TGFβ) pathways (Klüppel et al., 2002). Using a bioinformatical approach, conserved long-range cis-regulatory modules were identified in the CHST11 locus. Luciferase reporter assays identified a functional CHST11 promoter, as well as a number of cis-regulatory modules able to positively and negatively regulate CHST11 expression in a TGFβ-dependent as well as -independent manner (Willis et al., 2009).


Atlas Image
Schematic illustration of the protein structure of CHST11 with known motifs indicated. CHST11 contains a transmembrane domain (TMD) for anchorage in the Golgi membrane (encoded by exon III), and a large luminal catalytic domain harboring a sulfotransferase domain, which contains a 5-phosphosulfate site (PSB), a 3 phosphate binding site (PB), as well as four C-terminal N-glycosylation sites (N1-N4) (all encoded by exon IV).


The CHST11 protein contains 352 amino acids, and has an approximate molecular mass of 43 kDa. CHST11 is a single pass type II membrane-bound protein (Klüppel, 2010). CHST11 protein contains a transmembrane domain (TMD) for anchorage in the Golgi mebrane, a 5 phosposulfate binding site (PSB), a 3 phosphate binding site (PB), required for binding of the phosphate donor PAPS and transfer of sulfate groups, and four N-linked glycosylation sites (N1 to N4) in the C-terminal end of the protein.


CHST11 has a highly specific temporal and spatial expression pattern during mouse embryogenesis, and has been detected in notocord, heart valves and myocardium, apical ectodermal ridge during limb generation, neural tube, hair follicles, kidney, and proliferating chondrocytes in the cartilage growth plate during skeletal development (Klüppel et al., 2002; Klüppel et al., 2005). In adult tissues, CHST11 has been reported to be widely expressed, including in spleen, thymus, bone marrow, peripheral blood leukocytes, lymph node, heart, brain, lung and placenta (Habuchi and Miyashita, 1982; Hiraoka et al., 2000; Okuda et al., 2000; Yamauchi et al., 2000).


CHST11 is a single pass type II membrane-bound protein localized to the Golgi (Klüppel, 2010). However, CHST11 was initially identified as a protein secreted from chondrocytes and chondrosarcoma cells (Habuchi et al., 1991; Yamauchi et al., 1999).


Role in carbohydrate metabolism:
CHST11 catalyzes the transfer of sulfate from the universal intracellular sulfate donor PAPS (3-Phosphoadenosine 5-phosphosulfate) to the C4 position of the glycosaminoglycan chondroitin, generating chondroitin-4-sulfate (C4S) and adenosine 3,5-bisphosphate (Habuchi, 2000; Klüppel, 2010). Through a subsequent CHST11-independent enzymatic sulfation reaction, C4S can be transformed into the double-sulfated chondroitin sulfate-E (CS-E) (Habuchi, 2000; Klüppel, 2010). Different chondroitin sulfation forms have been shown to have distinct biological functions. CHST11 has also been shown to positively regulate chondroitin sulfate chain elongation (Anggraeni et al., 2011). N-glycosylation of CHST11 is required for its enzymatic function and heat stability (Yusa et al., 2005).

Role in cartilage development and osteoarthritis (OA):
Mouse CHST11 has been shown to be required for cartilage growth plate morphogenesis (Klüppel et al., 2005). Loss of CHST11 caused chondrodysplasia with severely shortened long bones, caused by shortened and thickened cartilage growth plates with disorganized and hypo-cellular cartilage growth plates with fibrillated ECM and an overall loss of chondroitin sulfate. Increased apoptosis of mutant chondrocytes was observed, and TGFbeta and BMP signaling was disturbed in mutant growth plates (Klüppel et al., 2005). Many of these cartilage deficiencies are characteristic of the degenerative alterations observed in OA, a degenerative disease characterized by loss of matrix GAGs and cartilage integrity. Increased CHST11 expression has been observed in OA (Zeggini et al., 2012). Combined, these data suggest a requirement for tightly controlled regulation of CHST11 expression in the development and maintenance of healthy cartilage.

Role in HSV infection:
Herpes simplex virus (HSV) envelope glycoproteins utilize cell-surface GAGs to efficiently bind to and infect host cells. The gC HSV envelope protein has been suggested to bind cell-surface CS-E-proteoglycans with high affinity, and treatment with exogenous CS-E could potently inhibit HSV infectivity, thus identifying CS-E chains of cell-surface proteoglycans as key receptors for HSV entry into a host cell. Deficiency in CHST11 expression leads to drastically reduced susceptibility to HSV infection in L-cell fibroblasts, presumably through the absence of CHST11-mediated CS-E synthesis (Uyama et al., 2006).

Role in malaria:
Malaria is caused by the parasites of the species Plasmodium, and is transmitted through infected mosquitos. High affinity adherence of P. falciparum-infected erythrocytes to endothelial cells is mediated by the CHST11 product C4S on endothelial cell-surface proteoglycans (Rogerson et al., 1995; Cooke et al., 1996; Pouvelle et al., 1997; Beeson et al., 1998).

Role in Costello syndrome:
Costello syndrome is a pediatric genetic disorder linked to oncogenic germline mutations in the HRAS gene (Gripp, 2005; Quezada and Gripp, 2007; Rauen, 2007; Gripp and Lin, 2012). The disease is characterized by multiple developmental abnormalities as well as predisposition to malignancies (White et al., 2005; Quezada and Gripp, 2007; Rauen et al., 2008). Reduction in CHST11 mRNA and protein expression, as well as loss of C4S has been identified in primary fibroblasts derived from Costello syndrome patients (Hinek et al., 2005; Klüppel et al., 2012). Oncogenic HRAS in normal fibroblasts can repress CHST11 expression, while interference with oncogenic HRAS signaling in these cells elevated CHST11 expression, thus identifying CHST11 as a negatively regulated target gene of HRAS signaling (Klüppel et al., 2012). Forced expression of CHST11 in Costello fibroblasts rescued the proliferation and elastogenesis defects associated with oncogenic HRAS signaling in these cells (Klüppel et al., 2012). These results indicate that reduced CHST11 expression and a subsequent chondroitin sulfation imbalance mediate the effects of oncogenic HRAS signaling in the pathogenesis of Costello syndrome.

Role in cancer:
Changes in CS levels and chondroitin sulfation balance have been described during tumor progression (Ricciardelli et al., 1997; Suwiwat et al., 2004; Theocharis et al., 2006; Sakko et al., 2008; Teng et al., 2008; Svensson et al., 2011; Vallen et al., 2012). Experimental elimination of chondroitin sulfate in orthotopic breast cancer mouse models lead to increased metastasis, demonstrating a critical role of chondroitin epitopes in tumor progression in vivo (Prinz et al., 2011). The CHST11 gene was highly expressed in aggressive breast cancer cells, but significantly less so in less aggressive breast cancer cell lines (Cooney et al., 2011). Moreover, a positive correlation was observed between the expression levels of CHST11 and P-selectin-mediated adherence of breast cancer cells to endothelial cells (Cooney et al., 2011). Increased expression of the CHST11 gene has been observed in multiple myeloma (Bret et al., 2009). One case report of a patient with B-cell chronic lymphocytic leukemia (B-CLL), a chromosomal translocation with breakpoints in the IGH locus on chromosome 14, and the CHST11 locus on chromosome 12 [t(12;14)(q23;q32)] was identified. The translocation breakpoint mapped to intron 2 of the CHST11 locus, and resulted in the expression of two truncated forms of CHST11 (Schmidt et al., 2004).

Role in Wnt-β-catenin signaling:
Studies were performed in mutant sog9 L-cell fibroblasts, which lack the expression of both EXT1 (Extosis-1, required for heparan sulfate biosynthesis) and CHST11 genes (Nadanaka et al., 2008). Mutant cells had a significant decrease in Wnt3a-stimulated β-catenin accumulation, which could be rescued by stably expressing CHST11, but not EXT-1 (Nadanaka et al., 2008). In addition, this study showed that the specific chondroitin sulfate form CS-E, but not the other chondroitin sulfate forms, was able to bind Wnt3a ligand with high affinity. Addition of CS-E to normal L-cells reduced β-catenin levels, much like what was seen in the sog9 mutant L-cells lacking CHST11 expression (Nadanaka et al., 2008). Together, this data suggested that the CHST11, through its ability to produce CS-E containing proteoglycans, might play a role in the Wnt/β-catenin signaling pathway. The investigators of this study suggested a model in which CHST11 expression increases the level of CS-E containing proteoglycans, which can then bind Wnt3a, and facilitate the binding of Wnt ligands to its receptor complex, thus increasing the efficiency of ligand-receptor interactions. In a follow-up study, Nadanaka et al. (2011) show that L-cells stably expressing the Wnt3a ligand had a reduction in CHST11 gene expression, and subsequently a change in sulfation balance with a higher concentration of chondroitin sulfate products with low affinity for Wnt3a ligand binding (Nadanaka et al., 2011). This allows the Wnt3a ligand to freely diffuse across L-cell fibroblast cultures. Forced expression of CHST11 was suggested to inhibit the diffusion of Wnt3a ligand in L-cell fibroblast cultures, because of the increase in production of CS-E containing proteoglycans (Nadanaka et al., 2011). These and previous studies suggested that CHST11 expression is able to inhibit Wnt3a diffusion and sustained signaling, but CHST11 gene expression is negatively regulated by active Wnt/β-catenin signaling (Nadanaka et al., 2011). We reported the identification of the CHST11 product CS-E as an inhibitor of specific molecular and biological outcomes of Wnt3a signaling in NIH3T3 fibroblasts (Willis and Klüppel, 2012). CS-E could decrease Wnt3a signaling through negative regulation of LRP6 receptor activation. However, this inhibitory effect of CS-E only affected Wnt3a-mediated induction, but not repression, of target gene expression (Willis and Klüppel, 2012). We went on to identify a critical Wnt3a signaling threshold that differentially affects target gene induction versus repression. This Wnt3a signaling threshold also differentially controlled the effects on proliferation and serum starvation-induced apoptosis (Willis and Klüppel, 2012). These data established the feasibility to manipulate the chondroitin sulfate biosynthesis machinery, in particular CHST11, to selectively inhibit Wnt/β-catenin transcriptional programs and biological outcomes through the exploitation of intrinsic signaling thresholds (Willis and Klüppel, 2012).


Homologous genes: CHST12, CHST13.



A chromosomal translocation t(12;14)(q23;q32) has been described in one patient with B-cell chronic lymphocytic leukemia (B-CLL) (Schmidt et al., 2004). Breakpoints of this have been mapped to the IGH locus on chromosome 14, and the CHST11 locus on chromosome 12 [t(12;14)(q23;q32)] (Schmidt et al., 2004). The translocation breakpoint mapped to intron 2 of the CHST11 locus, and resulted in the expression of three CHST11-IgH fusion transcripts (Schmidt et al., 2004). It was not determined whether these fusion transcripts lead to the expression of truncated CHST11 proteins, or whether the expression of the observed fusion transcripts might have any functional consequences on chondroitin sulfate biosynthesis and/or disease development or severity.
Atlas Image
CHST11-IgH fusion transcripts generated by a chromosomal translocation t(12;14)(q23;q32) in a patient with B-cell chronic lymphocytic leukemia. Fusions I and II retain 3 parts of the CHST11 coding sequence, including the sulfotransferase domain in exon IV. Fusion III retains the 5 part of the CHST11 transcript, including non-coding exons I and exon II, which encodes the transmembrane domain. Thus, fusions I and II are predicted to lack transmembrane domains, but retain sulfotransferase activity, whereas fusion III contains the CHST11 transmembrane domain, but lacks the sulfotransferase domain. The IgH components in all fusion transcripts are mainly non-coding sequences; the largest reading frame in the IgH-derived sequences are 36 bp in length (Schmidt et al., 2004). Figure adapted and modified from Schmidt et al., 2004.


This is a somatic mutation in B-CLL cells (Schmidt et al., 2004).

Implicated in

Entity name
B-cell chronic lymphocytic leukemia (B-CLL)
Translocation t(12;14)(q23;q32).
Hybrid gene
This translocation generates a IGH-CHST11 hybrid gene, with breakpoints in the IGH locus on chromosome 14, and the CHST11 locus on chromosome 12. A functional role of this hybrid gene in tumor progression has not been elucidated (Schmidt et al., 2004).
Entity name
Microarray analysis identified increased expression of a number genes involved in glycosaminoglycan biosynthesis, including CHST11 (Bret et al., 2009). The authors hypothesized that heparan sulphate and chondroitin sulphate side chains of the proteoglycan syndecan-1 play critical roles in mediating the biological changes from memory B cells to malignant plasma cells (Bret et al., 2009).
Entity name
Breast cancer
The CHST11 gene is highly expressed in aggressive breast cancer cells, but significantly less so in less aggressive breast cancer cell lines (Cooney et al., 2011). Moreover, a positive correlation was observed between the expression levels of CHST11 and P-selectin-mediated adherence of breast cancer cells to endothelial cells (Cooney et al., 2011).


Pubmed IDLast YearTitleAuthors
212849362011Correlation of C4ST-1 and ChGn-2 expression with chondroitin sulfate chain elongation in atherosclerosis.Anggraeni VY et al
96326111998Inhibition of binding of malaria-infected erythrocytes by a tetradecasaccharide fraction from chondroitin sulfate A.Beeson JG et al
192985952009Expression of genes encoding for proteins involved in heparan sulphate and chondroitin sulphate chain synthesis and modification in normal and malignant plasma cells.Bret C et al
89169711996Adhesion of malaria-infected red blood cells to chondroitin sulfate A under flow conditions.Cooke BM et al
216582542011Chondroitin sulfates play a major role in breast cancer metastasis: a role for CSPG4 and CHST11 gene expression in forming surface P-selectin ligands in aggressive breast cancer cells.Cooney CA et al
222617532012Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations.Gripp KW et al
160106792005Tumor predisposition in Costello syndrome.Gripp KW et al
69572471982Separation and characterization of chondroitin 6-sulfotransferase and chondroitin 4-sulfotransferase from chick embryo cartilage.Habuchi O et al
17515541991Secretion of chondroitin 6-sulfotransferase and chondroitin 4-sulfotransferase from cultured chick embryo chondrocytes.Habuchi O et al
109188172000[Biological function of chondroitin sulfate and sulfotransferases].Habuchi O et al
156377292005Myocardial storage of chondroitin sulfate-containing moieties in Costello syndrome patients with severe hypertrophic cardiomyopathy.Hinek A et al
107816012000Molecular cloning and expression of two distinct human chondroitin 4-O-sulfotransferases that belong to the HNK-1 sulfotransferase gene family.Hiraoka N et al
223179732012C4ST-1/CHST11-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome.Klüppel M et al
123511722002A high-throughput induction gene trap approach defines C4ST as a target of BMP signaling.Klüppel M et al
160791592005Maintenance of chondroitin sulfation balance by chondroitin-4-sulfotransferase 1 is required for chondrocyte development and growth factor signaling during cartilage morphogenesis.Klüppel M et al
208076432010The roles of chondroitin-4-sulfotransferase-1 in development and disease.Klüppel M et al
211231702011Down-regulation of chondroitin 4-O-sulfotransferase-1 by Wnt signaling triggers diffusion of Wnt-3a.Nadanaka S et al
110563882000Molecular cloning, expression, and chromosomal mapping of human chondroitin 4-sulfotransferase, whose expression pattern in human tissues is different from that of chondroitin 6-sulfotransferase.Okuda T et al
93079791997Chondroitin-4-sulfate impairs in vitro and in vivo cytoadherence of Plasmodium falciparum infected erythrocytes.Pouvelle B et al
221839492011Elimination of breast tumor-associated chondroitin sulfate promotes metastasis.Prinz RD et al
180259292007Costello syndrome and related disorders.Quezada E et al
184121222008Molecular aspects, clinical aspects and possible treatment modalities for Costello syndrome: Proceedings from the 1st International Costello Syndrome Research Symposium 2007.Rauen KA et al
172506582007HRAS and the Costello syndrome.Rauen KA et al
98157751997Elevated stromal chondroitin sulfate glycosaminoglycan predicts progression in early-stage prostate cancer.Ricciardelli C et al
77908151995Chondroitin sulfate A is a cell surface receptor for Plasmodium falciparum-infected erythrocytes.Rogerson SJ et al
187685202008Immunohistochemical level of unsulfated chondroitin disaccharides in the cancer stroma is an independent predictor of prostate cancer relapse.Sakko AJ et al
152737232004Deregulation of the carbohydrate (chondroitin 4) sulfotransferase 11 (CHST11) gene in a B-cell chronic lymphocytic leukemia with a t(12;14)(q23;q32).Schmidt HH et al
150731292004Expression of extracellular matrix components versican, chondroitin sulfate, tenascin, and hyaluronan, and their association with disease outcome in node-negative breast cancer.Suwiwat S et al
218503702011Chondroitin sulfate expression predicts poor outcome in breast cancer.Svensson KJ et al
184879972008Increased expression of non-sulfated chondroitin correlates with adverse clinicopathological parameters in prostate cancer.Teng YH et al
172397712006Chondroitin sulfate as a key molecule in the development of atherosclerosis and cancer progression.Theocharis AD et al
170409002006Chondroitin 4-O-sulfotransferase-1 regulates E disaccharide expression of chondroitin sulfate required for herpes simplex virus infectivity.Uyama T et al
227330952012Highly sulfated chondroitin sulfates, a novel class of prognostic biomarkers in ovarian cancer tissue.Vallen MJ et al
159407032005The adult phenotype in Costello syndrome.White SM et al
229155822012Inhibition by chondroitin sulfate E can specify functional Wnt/β-catenin signaling thresholds in NIH3T3 fibroblasts.Willis CM et al
199375892009Identification and characterization of TGFbeta-dependent and -independent cis-regulatory modules in the C4ST-1/CHST11 locus.Willis CM et al
107227462000Molecular cloning and expression of chondroitin 4-sulfotransferase.Yamauchi S et al
156289712005N-linked oligosaccharides are required to produce and stabilize the active form of chondroitin 4-sulphotransferase-1.Yusa A et al
227631102012Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.Zeggini E et al

Other Information

Locus ID:

NCBI: 50515
MIM: 610128
HGNC: 17422
Ensembl: ENSG00000171310


dbSNP: 50515
ClinVar: 50515
TCGA: ENSG00000171310


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfateKEGGko00532
Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfateKEGGhsa00532
Metabolism of carbohydratesREACTOMER-HSA-71387
Glycosaminoglycan metabolismREACTOMER-HSA-1630316
Chondroitin sulfate/dermatan sulfate metabolismREACTOMER-HSA-1793185
Chondroitin sulfate biosynthesisREACTOMER-HSA-2022870

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
192400612009Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.75
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
216582542011Chondroitin sulfates play a major role in breast cancer metastasis: a role for CSPG4 and CHST11 gene expression in forming surface P-selectin ligands in aggressive breast cancer cells.49
200806502010Inherited genetic variant predisposes to aggressive but not indolent prostate cancer.46
128470912003Specificities of three distinct human chondroitin/dermatan N-acetylgalactosamine 4-O-sulfotransferases demonstrated using partially desulfated dermatan sulfate as an acceptor: implication of differential roles in dermatan sulfate biosynthesis.26
211231702011Down-regulation of chondroitin 4-O-sulfotransferase-1 by Wnt signaling triggers diffusion of Wnt-3a.12
255115842015Regulation of chondroitin-4-sulfotransferase (CHST11) expression by opposing effects of arylsulfatase B on BMP4 and Wnt9A.7
260846102015Prognostic impact of chondroitin-4-sulfotransferase CHST11 in ovarian cancer.7
223179732012C4ST-1/CHST11-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome.6
255861912015CHST11 gene expression and DNA methylation in breast cancer.5


Michael Klüppel

CHST11 (carbohydrate (chondroitin 4) sulfotransferase 11)

Atlas Genet Cytogenet Oncol Haematol. 2014-04-01

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