[Frontiers in Bioscience E4, 499-515, January 1, 2012]
Sialyltransferases functions in cancers
Anne Harduin-Lepers1, Marie-Ange Krzewinski-Recchi1, Florent Colomb1, Francois Foulquier1, Sophie Groux-Degroote1, Philippe Delannoy1
1
TABLE OF CONTENTS
1. ABSTRACT
Abnormally elevated levels of sialylated tumor associated carbohydrate antigens are frequently described at the surface of cancer cells and/or secreted in biological fluids. It is now well established that this over-expression may result from deregulation in sialyltransferases enzymatic activity involved in their biosynthesis, but the precise molecular mechanisms remain unknown. Twenty different human sialyltransferases preside to the sialylation of glycoconjugates, either glycolipids or glycoproteins. This review summarizes the current knowledge on human sialyltransferases implicated in the altered expression of sialylated tumor associated antigens, the molecular basis of their regulated expression in cancer cells and the various tools developed by researchers and clinicians for their study in pathological samples.
2. INTRODUCTION
The oligosaccharide chains of glycoproteins and glycolipids of vertebrates are often terminated with sialic acids, a family of nine carbon monosaccharides derived from neuraminic acid (1, 2). These sialylated glycoconjugates at the cell surface mediate important biological roles and promote cell-cell interactions (3-6). In humans, sialylation of glycoconjugates is carried out by twenty sialyltransferases (ST), which catalyze the formation of different types of glycosidic linkages through an α2,3- or an α2,6-bond to galactose (Gal); an α2,6-bond to N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc), or through an α2,8-bond to another sialic acid, forming polysialic acid (reviewed in (7-9)). During neoplastic transformation, the activity of the Golgi-localized STs is usually increased (10) and as a consequence, cancer cells express more heavily sialylated tumor associated carbohydrate antigen (TACA) at their surface (11). In addition, increased sialylation and shortening of O-glycosylproteins glycan chains is also observed (12, 13) as well as reduced O-acetylation of sialic acid (14, 15). This aberrant sialylation of glycoconjugates mediate key pathological events during tumor progression, including invasion and metastasis. These specific over-expressed sialylated glycans are useful prognostic markers of malignant disease states. Cancer biomarkers like sialyl-Lewisa (sLea) epitope, known as the CA19-9 (Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAc) and sialyl-Tn (sTn) epitope, known as the CA72.4 (Neu5Acα2-6GalNAc) (16) have been used as targets for cancer immunotherapy in preclinical and clinical vaccine evaluation (17). However, most of the time, the mechanisms explaining observed altered sialylation in cancer cells remain unknown and no obvious correlation can be established between the enzymatic activity and the appearance of sialylated TACA. This review focuses on human ST implicated in the biosynthesis of the sialylated TACA and their role in cancer. In particular, we briefly review the tools of investigation available for researchers and clinicians and the proposed underlying mechanisms regulating aberrant expression of sialylated TACA in cancer are discussed.
3. HUMAN ST INVOLVED IN THE SYNTHESIS OF SIALYLATED TACA
Twenty sialyltransferases have been cloned from human sources (Table 1). The use of these ST cDNAs for recombinant protein production has shed light on their substrate specificity in vitro, although one should keep in mind that these enzymes might have slightly different enzymatic characteristics in vivo.
3.1. The β-galactoside α2,3-sialyltransferases (ST3Gal)
Six β-galactoside α2,3-sialyltransferases cDNAs (reviewed in (7, 8) have been identified and cloned from the human genome (Table 1). These enzymes catalyze the transfer of sialic acid in α2,3-linkage to terminal Gal residues found on glycoproteins or glycolipids.
ST3Gal I and ST3Gal II use almost exclusively type III disaccharide Galβ1-3GalNAc found onto O-glycosylproteins (core1) and glycolipids (asialo-GM1, GM1a and GD1b) (18, 19). ST3Gal I has also a little enzymatic activity towards type I disaccharide (Galβ1-3GlcNAc) (20, 21). The human ST3Gal I leads to the formation of Neu5Acα2-3Galβ1-3GalNAc, whereas the mouse ST3Gal I has a preference for glycolipid acceptors catalyzing the biosynthesis of the gangliosides GM1b, GD1a and GT1b at least in in vitro assays (22). The human ST3Gal II isolated from the human T-cell lymphoblast-like cell line (CEM T-cells) shows activity towards both glycolipids and glycoproteins (23) and may have a recognition site for the ceramide moiety in addition to the one for the Galβ1-3GalNAc moiety (24). ST3Gal I enzymatic activity is elevated in breast cancer compared to normal tissues and correlates with the grade of the tumor, whereas ST3Gal II is poorly expressed in breast tumors (25-28). ST3Gal I has been implicated in the increased expression of sialylated Thomsen-Friedenreich antigen (Neu5Acα2-3Galβ1-3GalNAc, sT antigen) observed in breast cancer cell lines and bladder cancer (29), whereas ST3Gal II mRNA is decreased (Figure 1). Altered mRNA expression of these STs was also shown to be of importance in malignant epithelial ovarian cancers (30, 31), in colon carcinoma (32) and correlated with poor prognosis in breast cancer (33, 34).
ST3Gal III, ST3Gal IV and ST3Gal VI show similar enzymatic specificity catalyzing the transfer of sialic acid on the terminal Gal residue of the disaccharide Galβ1-3/4GlcNAc of glycoproteins or glycolipids. The human ST3Gal III uses preferentially type I disaccharide Galβ1-3GlcNAc and therefore represents the most probable candidate for the in vivo biosynthesis of sLea (35). The human ST3Gal IV and ST3Gal VI use preferentially Galβ1-4GlcNAc disaccharide as acceptor substrate (36-38) probably carried by different substrates in the glycoproteome of the cell (39) leading to the formation of sialyl-Lewisx (sLex) epitope (Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAc). In addition, human ST3Gal IV could also contribute to the sT antigen synthesis in breast cancer cells and tumors (33, 34, 36) and ST3Gal VI would be involved in the sialyl-3-paragloboside (Neu5Acα2-3Galβ1-4GlcNAcβ1-4Galβ1-4Glcβ1-Cer) biosynthesis, a precursor of the sLex on ceramide (CD75s) (Figure 1) (37). Aberrant expression of Lewis-type antigens has been reported in many types of cancers, including lung, colon, kidney, stomach (reviewed in (40)), breast and gastric cancers in which their expression levels are regulated by differential expression of these α2,3-sialyltransferases (39, 41). Over-expression of ST3Gal III in pancreatic cells modulates motility and invasion and enhances metastatic potential (42). Finally, the recombinant human ST3Gal V (43) uses almost exclusively lactosyl-ceramide (LacCer, Galβ1-4Glcβ1-Cer) as an acceptor substrate giving rise to GM3, and is also known as the GM3-synthase (Table 1). Interestingly, Berselli et al. reported on the expression of N-terminal 33 amino acids extended isoform of the human ST3Gal V in placenta, which uses (LacCer) and also galactosyl-ceramide (Galβ-Cer), GA1 and asialoganglioside GA2 (GalNAcβ1-4Galβ1-4Glcβ-Cer) (44). GM3 is also associated with cancer and recently, ST3Gal V mRNA level was found to be increased in pediatric leukemia (45).
3.2. The β-galactoside α2,6-sialyltransferases (ST6Gal)
β-galactoside α2,6-sialyltransferases ST6Gal I and ST6Gal II catalyze the transfer of sialic acid mainly to the terminal Gal residue of type II disaccharide through an α2,6-linkage giving rise to the formation of the Neu5Acα2-6Galβ1-4GlcNAc- (Sia6LacNAc) found on N-glycosylproteins and to a lesser extent, on O-glycosylproteins, glycolipids and free oligosaccharides (7, 46, 47). The recombinant human ST6Gal I produced in eukaryotic cells shows a broad substrate specificity towards Gal(NAc)β1-4GlcNAc bearing substrates (Table 1) (48). ST6Gal I is also responsible for the biosynthesis of a unique human colon cancer biomarker candidate named α2,6-sialylated blood group type 2H (ST2H) antigen (Fucα1-2(Neu5Acα2-6)Galβ1-4GlcNAcβ1-3Galβ1-4Glc-Cer) (49). Human ST6Gal II exhibits in vitro a more restricted substrate specificity towards a few Galβ1-4GlcNAc and GalNAcβ1-4GlcNAc bearing glycoconjugates that are not identified yet (48, 50-52). Enhanced expression of Sia6LacNAc has been reported in numerous carcinoma such as colon, breast, cervix, choriocarcinoma, acute myeloid leukemia and brain tumors (34, 53-61). Elevated ST6Gal I mRNA levels have been described in pediatric leukemia (45).
3.3. The GalNAc α2,6-sialyltransferases (ST6GalNAc)
Six different human GalNAc α2,6-sialyltransferases catalyze the transfer of sialic acid residues in α2,6-linkage to the proximal GalNAc residue of O-glycosylproteins (ST6GalNAc I, ST6GalNAc II, ST6GalNAc IV) or onto GalNAc residues of glycolipids like GM1b (ST6GalNAc III, ST6GalNAc V, ST6GalNAc VI) (7).
Recombinant ST6GalNAc I and ST6GalNAc II proteins have similar enzymatic activity in vitro, catalyzing the transfer of sialic acid onto GalNAc residues of the type III disaccharide Galβ1-3GalNAc-peptide (α2,3-sialylated or not) of mucin-type glycoproteins (19) (Table 1). Their activity depends on the peptide moiety (62, 63). ST6GalNAc I is also known as the sTn synthase. Higher ST6GalNAc I and sTn antigen expression is a marker of malignancy with a poor prognosis in many epithelial cancers like gastric, pancreatic, colorectal, ovarian and breast cancers (17, 26, 41, 64-67).
The human ST6GalNAc III and ST6GalNAc IV show the most restricted substrate specificity using exclusively the Neu5Acα2-3Galβ1-3GalNAc- trisaccharide found on either O-glycosylproteins or ganglioside GM1b, which suggests that they do not discriminate between α- and β-linked GalNAc (68, 69) (Table 1). Interestingly, Tsuchida et al. have proposed indirect involvement of ST6GalNAc VI in synthesizing disialyl lactotetraosyl-ceramide (Lc4), a precursor of disialyl-Lewisa (disialyl Lea) (Figure 1) (70). Indeed, the human ST6GalNAc VI and to a lesser extent ST6GalNAc V and ST6GalNAc III also catalyze the transfer of a sialic acid residue onto GlcNAc residues (70, 71). It has been shown recently that the expression of ST6GalNAc V in breast cancer cells enhanced their adhesion to brain endothelial cells and their passage through the blood-brain barrier (72). In addition, over-expression of ST6GalNAc V in glioma cells suppresses glioma invasivity in vivo and tumor formation in vitro (73). ST6GALNAC6 gene expression in colon cancer cells is down regulated compared to non malignant epithelial cells thereby contributing to the increased expression of sLea (74).
3.4. The α2,8-sialyltransferases (ST8Sia)
The six members of the human ST8Sia family catalyze the transfer in α2,8-linkages of one to several sialic acids to another sialic acid of glycoproteins or glycolipids (7).
ST8Sia I, ST8Sia V and ST8Sia VI can be viewed as mono-α2,8-sialyltransferases, since they catalyze the transfer of a unique sialic acid residue in α2,8-linkage (Table 1). ST8Sia I, which shows a strict specificity towards GM3 resulting in the formation of GD3, is also known as GD3-synthase (Figure 1). However, Nara et al. reported the molecular cloning of a short isoform of the human ST8Sia I (341 amino acids) using other gangliosides as acceptor substrates yielding to the formation of GD3 and also GD1c, GT1a and GQ1b in vitro (75), whereas Nakayama et al. reported the molecular cloning of a long isoform of the human ST8Sia I (356 amino acids) with an extended cytoplasmic domain capable of using GD3 to form GT3 in vitro (76). The human ST8Sia V also known as the GT3-synthase (77) sialylates different gangliosides such as GD3, GM1b, GD1a, GT1b and GQ1c (Table 1) (9, 78). The human ST8Sia VI catalyzes the transfer of a single sialic acid residue mainly on α2,3-sialylated O-glycans of glycoproteins (Neu5Acα2-3Galβ1-3GalNAc-) and also to a lesser extent on α2,6-sialylated O-glycosylproteins (Galβ1-3(Neu5Acα2-6)GalNAc-) leading to the formation of diSia motifs (79). The mouse st8sia6 gene was found to be upregulated in lung dysplasia induced by c-Raf-1 (80).
The human ST8Sia III (81) catalyzes the transfer of one to several sialic acid residues either on glycoproteins or glycolipids (82, 83) and can be viewed as an oligo-α2,8-sialyltransferase (84). ST8Sia III is thought to be implicated in the biosynthesis of GT3 and disialyl-motifs found on CD-166 (Table 1) (85).
The human ST8Sia II and ST8Sia IV (86-88) catalyze the transfer of several sialic acid residues on other sialylated glycoconjugates. Both enzymes are expressed in the nervous system of most vertebrates where they act mainly on the α2,3-sialylated N-glycans of N-CAM (89-91) resulting in an increased neuronal plasticity and migration in embryonic vertebrate embryos (92). High levels of poly-sialic acid chain (PSA) are re-expressed in tumors of neuroectodermal origin and in small cell lung carcinoma (88).
4. INVESTIGATIONS-TOOLS TO STUDY SIALYLATION CHANGES AND STs IN CANCER
Lectin histochemistry and immunohistochemistry and various combinations of these methods are widely used to discover aberrant sialylation patterns serving as markers for tumor progression and metastasis and to develop new methods for diagnosis. In addition, several strategies have been developed to investigate variations in ST enzymatic activities and level of gene expression in cancer tissues.
4.1. Linkage and sialylated products formed: Use of lectins and antibodies
Since sialylated TACA may have a low expression level or a restricted expression pattern, lectins have proven useful tools in investigating sialic acid pattern of expression as well as diversity and linkages in normal and cancer cells and tissues (5, 93). As summarized in Table 2, the Sambuccus nigra agglutinin (SNA) detects the Neu5Acα2-6Gal-R oligosaccharides synthesized by β-galactoside α2,6-sialyltransferases and to a lesser extent, Neu5Acα2-6GalNAc-R oligosaccharides synthesized by GalNAc α2,6-sialyltransferases. Seeds from Maackia amurensis (MAA) contain two lectins that exhibit different specificity towards sialylated terminal structures: the leukoagglutinin preferentially binds to the Neu5Acα2-3Galβ1-4GlcNAc- oligosaccharide, whereas the hemagglutinin shows a higher affinity for the Neu5Acα2-3Galβ1-3(Neu5Acα2-6))GalNAc oligosaccharide (94). The animal Limax flavus agglutinin (LFA) and the Limulus polyphemus agglutinin (LPA) are specific for terminal Neu5Ac and Neu5Gc in α2,3-, α2,6-, or α2,8-linkages (95, 96). The wheat germ agglutinin (WGA) is also frequently used although its specificity has to be confirmed by sialidase treatment, since it also binds terminal GlcNAc residues (97). The peanut agglutinin (PNA) from Triticum vulgaris recognizes non-sialylated T antigens obtained after sialidase treatment of human normal and cancer tissues section (29, 98). In addition to lectin histochemistry on tissue sections or fixed cells, Western or dot-blot for glycoprotein analysis, as well as thin layer chromatography for detection of gangliosides are carried out with lectins (99). Other sialic acid recognizing proteins have been used such as selectins, recombinant siglecs, the cholera toxin, which is a routine reagent staining the GM1 ganglioside and the hemagglutinin-esterase protein of influenza C virus, which specifically detects 9-O-acetylated sialic acid residues (100).
Whole cancerous cells have been used to immunize mice to generate monoclonal antibodies (mAbs) to various sialylated TACA, which serve for the detection of different types of sialic acid residues and linkages. Most of these antibodies are extremely specific and discriminate between various types of sialic acids (Neu5Ac or Neu5Gc) when carried by a given underlying oligosaccharide chain. Some mAbs are raised against sialylated O-glycans, like the sTn antigen overexpressed in cancers and their clinical usefulness for evaluating its levels in cancer patients is well documented (for review: (17)). MAbs recognizing cancer-associated terminal sialylated structures are also available, such as those against sLex and sLea tetrasaccharides carried by N- or O-glycosylproteins and some glycolipids. CA19-9 is the most common serum tumor marker for diagnosis of cancers of the gastro-intestinal tract (101). Noteworthy, sialic acid modifications such as O-acetylation might prevent mAb recognition. Since O-acetylation is significantly reduced in colon cancer, it contributes to the marked increase of detected sialic acid. Anti-gangliosides mAbs are widely used to probe their distribution in cells and tissues (102) as for the disialoganglioside GD3, which is over-expressed in neuroblastoma, melanoma and also breast cancer (103). Other gangliosides, i.e. 9-O-acetyl-GD3 and N-glycolyl-GM3, are also abnormally expressed in breast tumors (104). Specific antibodies against all these sialylated glycolipids are available and allow their detection and quantification in cancers, which is the first step to understand their function.
4.2. ST enzymatic activities and ST mRNAs: Use of enzymatic assays, Q-PCR, microarrays
In vitro enzymatic assays, using exogenous acceptor and radiolabeled donor (CMP-Neu5Ac) substrates are carried out to compare ST activities in tumor samples and in healthy tissues. For example, increased level of ST6Gal I activity and expression of its product, the CDw75 antigen Neu5Acα2-6Galβ1-4GlcNAc- have been described in malignant and transitional tissue in human colorectal cancer compared to healthy mucosa with asialotransferrin and N-acetyllactosamine as exogenous acceptors (105). In gastric cancer, high levels of ST3Gal III and ST6Gal I activities correlated with secondary local tumor recurrence (106). However, some discrepancies might be observed between ST activities measured in vitro and the sialylated products detected in cancer versus healthy tissues. This can be explained at least in part by overlapping ST activities towards the same acceptor acquired during vertebrate STs evolution (8, 47, 107).
Relevance of STs in cancer is frequently evaluated at the mRNA level. Multiplex RT-PCR analysis of five human ST genes in breast cancer biopsies showed that ST3GAL3 and ST6GAL1 gene expression was associated with a poor prognosis (34). Moreover, a high ST3GAL3/ST6GAL1 gene expression ratio associated to a high sE-selectin concentration correlated with reduced relapse-free and overall survival of node-negative patients (108). These data suggest that sLea and sLex motifs at the surface of cancer cells could be recognized by endothelial cells E-selectin, favoring metastasis formation. Mondal et al. demonstrated that ST6GAL1 and ST3GAL5 mRNAs were up-regulated in pediatric acute leukemia lymphoblasts and positively correlated with a higher risk of disease, whereas their expression was negligible in non-malignant donors (45). Similarly, ST8SIA2 gene is highly expressed in various stages of neuroblastoma tumors suggesting its potential clinical relevance as a molecular marker of metastatic neuroblastoma (109). In most of these studies, authors correlated ST mRNA levels to the detection of specific sialylated TACA in healthy vs. cancer tissues. The increased ST3GAL1 expression contributes to the higher level of a2,3-sialylation found in ovarian serous carcinoma (31). Similarly, over-expression of ST3GAL1 involved in T antigen sialylation appears to be part of the initial oncogenic transformation of bladder cells thus predicting cancer progression and recurrence (29). However, correlation between ST gene expression and sialylated determinants is not always observed. For example, sTn is over-expressed in 30 % of breast tumors and considered as a bad prognosis factor (17) whereas the expression of ST6GALNAC1 involved in the sTn biosynthesis has been associated with a better prognosis in breast cancer (110).
Microarrays followed by Q-PCR validation provide another method for monitoring ST mRNA expression levels simultaneously in primary tumors and cell lines. A Human Whole Genome Oligo Microarrays was used to investigate genes differentially expressed in early- and late-stage oral squamous cell carcinoma. ST6GAL1 was up-regulated in early stages of the disease and could be involved in local tumor invasion and metastasis (111). Differences in the expression of ST8SIA1 in breast cancer cells were investigated using microarray data of 1,581 tumor samples. Among estrogen receptor (ER) positive breast cancers, a significant worse prognosis was found for patients with tumors showing a low ST8SIA1 expression (112). The GeneChip analysis of colonic tissue of healthy individuals compared with early staged colonic carcinomas proved a high expression level of ST6GAL1 in colonic carcinomas, and showed that ST3GAL4 was the most abundantly expressed ST gene in healthy tissues (113). A more focused microarray analysis of glyco-gene expression was performed in human glioma showing a low level of ST6GALNAC5 in glioma compared to normal brain (73, 114).
4.3. Use of chemical inhibitors of ST activities and ST antisense oligodeoxynucleotides
Chemical inhibitors of STs are used to analyze the role of sialylation in cancer progression and metastases and serve as new potent anti-inflammatory, immunosuppressive and anti-metastatic agents for future therapeutic applications. Soyasaponin I, a natural molecule isolated from soybean, is the first described CMP-Neu5Ac competitive inhibitor of ST3Gal I in vivo (115). Over the past two decades, efforts have been made to design and synthesize specific ST inhibitors such as donor- and acceptor-substrate based analogs or compounds with a structural mimetic of transition-state (for review: (116-118)). Although these compounds are effective inhibitors in vitro, they are less efficient in vivo due to a poor permeability across cell membranes. Only a few of them with a cell-permeable property have been reported so far (119, 120). Among these compounds, the ST inhibitor KI-8110 (5-fluoro-2',3'-isopropylidene-5'-O-(4-N-acetyl-2,4-dideoxy-3,6,7,8-tetra-O-acetyl-1-methoxycarbonyl-D-glycero-α-D-galactooctapyranosyl) uridine), a donor-analog, efficiently lowered pulmonary metastatic potential of murine NL-17 colon adenocarcinoma cells (121) by inhibiting platelet-derived growth factor-(PDGF) dependent growth of cancer cells (122). Lithocholic acid analogues with a steroid-related structure similar to that of Soyasaponin I, were found to be noncompetitive inhibitors of Galβ1-3GalNAc α2,3-sialyltransferases (123). Among the lithocholic acid derivatives, AL10 inhibits adhesion, migration and invasion of ST3Gal I over-expressing A549 and CL1.5 human lung cancer cells, associated with reduced integrin signaling and it also significantly suppresses experimental lung metastasis (124). Lith-O-Asp, another lithocholic acid derivative, suppresses cell tumor metastasis /colonization in vitro and in vivo through degradation of ST proteins (125). Finally, competitive inhibitors of O-glycosylation such as benzyl-N-acetyl-α-D-galactosaminide (BGN) inhibit O-linked oligosaccharide sialylation in cancer cells (126). BGN treatment results in a decreased CD44 O-glycan sialylation and enhanced metastatic ability of B16BL6 melanoma cells (127).
Specific inhibition of STs by antisense or small hairpin RNA is useful to analyze their role in cancer. Antisense silencing of ST8Sia I in F-11 rat neuroblastoma cells greatly reduces cell proliferation, angiogenesis, vascular endothelial growth factor (VEGF) production and tumor growth in nude mice (128, 129). Similarly, ST8Sia I antisense knockdown reduces cell growth in the hamster melanoma AbC-1 cell line (130). Significant decrease of cell growth and invasion activity is also observed in lung cancer cells, when stably transfected with a ST8Sia I RNAi expression vector (131). In parallel, ST3Gal V silencing in 4T1 highly metastatic mouse mammary tumor cells significantly inhibits cell migration, invasion and anchorage-independent growth in vitro, and lung metastasis in vivo, through the activation of PI3K/Akt pathway and nuclear factor of activated T cells (NFAT) inhibition (132). ST6Gal I is known to be up-regulated in several human cancers, including breast and colon cancers. Transfection of MDA-MB-435 cancer cells with ST6Gal I cDNA increases cell surface α2,6-sialylation and cell migration and reduces cell-cell adhesion. Antisense ST6Gal I RNA significantly decreased collagen IV and cell-extracellular matrix adhesion (133), suggesting that cell surface α2,6-sialylation contributes to extracellular matrix adhesion of tumor cells. It has been also reported that ST6Gal I silencing strongly reduces the ability of HT-29 human colon cancer cells to form colonies in soft agar and to invade the extracellular matrix (134).
5. MECHANISMS OF ST REGULATION
The relative enzymatic activity of STs influences the expression of sialylated TACA at the cell surface and contributes to the definition of the glycosylation pattern of normal and tumor cells. STs spatio-temporal expression appears to be regulated mainly at the transcriptional level although epigenetic and posttranslational controls might be implicated.
5.1. Genetic regulation: transcriptional regulation of ST
Multiple approaches including Q-PCR, microarray analysis, enzymatic assays, as well as Northern blot and in situ hybridization have demonstrated a correlation between ST mRNA expression and enzymatic activity, suggesting that the synthesized sialylated structures mostly depend on transcriptional regulation of ST genes (135). In the past decades, several studies have documented the structure, genomic organization as well as transcriptional regulation of human ST genes in cultured cells (for review see (7, 136)). Multiple mRNA isoforms that differ essentially in their 5'-untranslated (5'-UT) regions have been described for several ST genes, most of which being tissue or cell type-specific. These mRNA isoforms usually arise from a combination of alternative splicing and promoter use, leading to a complex tissue or cell-specific transcriptional regulation of ST genes. Among these, ST6GAL1 genetic regulation has been the most studied. Mammalian st6gal1 genes share a common genomic organization with five coding exons (137-140). Sequence analysis of the 5'-flanking genomic region revealed heterogenous transcriptional start sites (TSS), at least three physically distinct promoters named P1, P2 and P3 and the absence of the canonical TATA and CCAAT boxes. These promoters govern and regulate the expression of multiple human ST6GAL1 mRNAs resulting from the combinatory use of seven 5'-UT exons named E1', EX, EY, EZ, EU, EV and EW (reviewed in (7)). RT-PCR analysis of carcinoma samples with an increased ST6Gal I activity compared to normal mucosa revealed the presence of at least two transcripts: the ubiquitously expressed transcript with the EY and EZ 5'-UT exons arising from P3 promoter and the hepatic specific transcript with the E1' 5'-UT exon arising from the P1 promoter. Both ST6Gal I transcripts were detectable in normal and cancer tissues, but the hepatic specific transcript had a marked tendency to accumulate in cancer (141, 142). This might be explained by the fact that P1 promoter shows binding site for the hepatocyte nuclear factor HNF-1 transcription factor, which is expressed not only in liver, but also in colon cancer tissues (143). In cervical squamous carcinoma cells, an increased level of ST6GAL1 hepatic transcripts has been described that may have an impact in cancer transformation (144). Similarly to ST6GAL1 gene, the ST6GAL2, ST3GAL2, ST3GAL4, ST3GAL5 and ST3GAL6 genes show also several 5'-UT exons and heterogeneous TSS leading to several mRNA isoforms. It is interesting to note that the other ST genes like ST3GAL1, ST3GAL3, all the ST6GALNAC and all the ST8SIA genes described up to date display a unique promoter region and ubiquitous transcription factors binding sites. These regulatory units drive the expression of unique mRNA or alternatively internally spliced RNA (reviewed in (7)) as described recently for the human ST8SIA1 gene (145-147)).
5.2. Epigenetic regulation
The transcriptional control of ST gene expression is not sufficient to fully explain the observed induction of sialylated TACA in cancer (25, 148-152). Recently, DNA hypermethylation or histone modifications have been recognized as one of the important mechanisms for gene inactivation in cancer (153). Indeed, addition of a histone deacetylase inhibitor trichostatin A and the DNA methylation inhibitor 5-azacytidine (5-aza-C) to the culture medium of sLea positive human colon cancer cells induces significant transcription of ST6GALNAC6 and surface expression of disialyl-Lea epitope (74, 101). These data suggest an epigenetic silencing mechanism for the ST6GALNAC6 gene expression leading to the decreased expression of the disialyl-Lea epitope in cancer cells, but resulting in an enhanced accumulation of sLea in cancer cells (154). Kawamura and co-workers have shown that among gastric cancer-associated down-regulated glycogenes, the ST3GAL6 gene was hypermethylated in most gastric cancer cell lines and in gastric cancer tissues causing silencing of the enzymatic activity of this enzyme (155). In addition, colon carcinoma HCT15 cells treated with Decitabine (5-aza-2'-deoxycytidine: 5-Aza-dC) showed enhanced production of sLex on MUC1 through induction of ST3GAL6 gene leading to increased binding to E-selectin and higher metastatic potential of these cells. These recent data raise a concern about the safety of 5-Aza-dC used for cancer treatment (156). Finally, data from microarray analysis showing candidate genes with greatest fold changes in expression after treatment with 5-aza-C in neuroblastoma described ST3GAL2 gene as one of these genes, although no CpG methylation could be detected (157).
5.3. Post-translational modifications and Golgi pH influence on ST intracellular location and activity
A number of studies have also suggested that post-translational modifications of STs such as phosphorylation or N-glycosylation and Golgi microenvironment could influence ST enzymatic activities (158). Resulting perturbations of sialylation efficiency might be secondary to disturbances in the assembly line of ST in the Golgi. The human ST6Gal I is expressed as two differentially phosphorylated protein isoforms, ST-Tyr and ST-Cys, which exhibit differences in catalytic activity and trafficking through the secretory pathway (159, 160). The enzymatic activity of STs implicated in the biosynthesis of gangliosides can be modulated by protein kinase C and phosphoprotein phosphatase (161). N-glycosylation of STs is also known to influence their enzymatic activity and subcellular location (162). Indeed, depletion of N-glycan by site directed mutagenesis of the sequon NXS/T or by treatment with glycosylation inhibitors like tunicamycin or castanospermine often leads to a reticulum re-distribution, an increased turn-over and hence a loss of enzyme activity of STs (163-170). Recently, it has been proposed that variations in the Golgi pH as observed in cancer cells (171, 172) might be partly responsible for abnormal sialylation observed in cancer cells (173) as for unsialylated MUC1 found in breast cancer cells (27, 150, 152) despite elevated levels of ST3Gal I (174). The link between Golgi pH and mislocalization of Golgi STs was recently highlighted by Rivinoja et al. especially for the α2,3-sialyltransferase ST3Gal I where a severe mislocalization into endosomal compartments was observed after drug-induced Golgi pH increase. At the opposite, ST6Gal I subcellular location and enzymatic activity remained almost unaffected (175). Another interesting parameter that could regulate ST activity in cancer is the interaction of STs among themselves with the formation of active homodimers or as complexes of several partners (oligomerization) through cysteine residues, as already shown for ST6Gal I (176-179).
6. CONCLUSION
Increased expression of sialylated TACA is a common feature observed at the surface of cancer cells that correlates most of the time to an altered expression of the corresponding STs involved in their biosynthesis. The molecular mechanisms governing sialylated TACA biosynthesis are not yet fully understood. Besides genetic and epigenetic regulation of STs, the leading causes of STs up- and down-regulation, posttranslational modifications of STs themselves and their arrangement along the secretory pathway appear to be essential factors controlling sialylated TACA biosynthesis. The resulting changes in sialylation are known to play key roles in cancer cell growth, invasion and metastasis. TACA provide a major source of cancer and prognostic biomarkers characterized by clinicians through the use of a panel of powerful tools such as monoclonal antibodies or lectins.
7. ACKNOWLEDGEMENTS
This work was financially supported by the University of Lille Nord de France, Lille1, the CNRS, l'ANR 2010BLAN 1204 01, la ligue contre le cancer, the Association pour la recherche sur le cancer (grant n�7936 and 5023).
8. REFERENCES
1.T. Angata & A. Varki: Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective. Chem Rev, 102, 439-469 (2002)
doi:10.1021/cr000407m
2.R Schauer & JP Kamerling: Chemistry,biochemistry and biology of sialic acids. In: Glycoproteins II. Eds: J Montreuil, JFG Vliegenthart&H Schachter. Elsevier, Amsterdam (1997)
doi:10.1016/S0167-7306(08)60624-9
3.S. Kelm & R. Schauer: Sialic acids in molecular and cellular interactions. Int Rev Cytol, 175, 137-240 (1997)
doi:10.1016/S0074-7696(08)62127-0
4.A. Varki: Sialic acids as ligands in recognition phenomena. Faseb J, 11, 248-255 (1997)
5.N. M. Varki & A. Varki: Diversity in cell surface sialic acid presentations: implications for biology and disease. Lab Invest, 87, 851-857 (2007)
doi:10.1038/labinvest.3700656
6.R. Schauer: Sialic acids as regulators of molecular and cellular interactions. Curr Opin Struct Biol, 19, 507-514 (2009)
doi:10.1016/j.sbi.2009.06.003
7.A. Harduin-Lepers: Comprehensive Analysis of sialyltransferases in vertebrate genomes. Glycobiology Insights, 2, 29-61 (2010)
8.A. Harduin-Lepers, R. Mollicone, P. Delannoy & R. Oriol: The animal sialyltransferases and sialyltransferase-related genes: a phylogenetic approach. Glycobiology, 15, 805-817 (2005)
doi:10.1093/glycob/cwi063
9.A. Harduin-Lepers, V. Vallejo-Ruiz, M. A. Krzewinski-Recchi, B. Samyn-Petit, S. Julien & P. Delannoy: The human sialyltransferase family. Biochimie, 83, 727-737 (2001)
doi:10.1016/S0300-9084(01)01301-3
10.F. Dall'Olio & M. Chiricolo: Sialyltransferases in cancer. Glycoconj J, 18, 841-850 (2001)
doi:10.1023/A:1022288022969
11.S. Hakomori: Aberrant glycosylation in tumors and tumor-associated carbohydrate antigens. Adv Cancer Res, 52, 257-331 (1989)
doi:10.1016/S0065-230X(08)60215-8
12.B. J. Campbell, I. A. Finnie, E. F. Hounsell & J. M. Rhodes: Direct demonstration of increased expression of Thomsen-Friedenreich (TF) antigen in colonic adenocarcinoma and ulcerative colitis mucin and its concealment in normal mucin. J Clin Invest, 95, 571-576 (1995)
doi:10.1172/JCI117700
13.S. H. Itzkowitz, A. Marshall, A. Kornbluth, N. Harpaz, J. B. McHugh, D. Ahnen & D. B. Sachar: Sialosyl-Tn antigen: initial report of a new marker of malignant progression in long-standing ulcerative colitis. Gastroenterology, 109, 490-497 (1995)
doi:10.1016/0016-5085(95)90337-2
14.S. Ogata, I. Ho, A. Chen, D. Dubois, J. Maklansky, A. Singhal, S. Hakomori & S. H. Itzkowitz: Tumor-associated sialylated antigens are constitutively expressed in normal human colonic mucosa. Cancer Res, 55, 1869-1874 (1995)
15.J. R. Jass, L. M. Allison & S. Edgar: Monoclonal antibody TKH2 to the cancer-associated epitope sialosyl Tn shows cross-reactivity with variants of normal colorectal goblet cell mucin. Pathology, 26, 418-422 (1994)
doi:10.1080/00313029400169301
16.C. A. Reis, H. Osorio, L. Silva, C. Gomes & L. David: Alterations in glycosylation as biomarkers for cancer detection. J Clin Pathol, 63, 322-329 (2010)
doi:10.1136/jcp.2009.071035
17.S. Julien & P. Delannoy: Sialyl-Tn antigen in cancer: from diagnosis to therapy. Recent Res. Devel. Cancer, 5, 185-199 (2003)
doi:10.1038/sj.bjc.6605083
18.H. Kitagawa & J. C. Paulson: Differential expression of five sialyltransferase genes in human tissues. J Biol Chem, 269, 17872-17878 (1994)
19.S. Groux-Degroote, A. Harduin-Lepers & P. Delannoy: Biosynthesis of mucin O-glycan chains in normal and pathological states. In: The epithelial Mucins: Structure/Function. Roles in Cancer and Inflammatory Diseases. Ed: I Van Seuningen. Research Signpost, Kerala, India (2008)
20.H. Ito, N. Hiraiwa, M. Sawada-Kasugai, S. Akamatsu, T. Tachikawa, Y. Kasai, S. Akiyama, K. Ito, H. Takagi & R. Kannagi: Altered mRNA expression of specific molecular species of fucosyl- and sialyl-transferases in human colorectal cancer tissues. Int J Cancer, 71, 556-564 (1997)
doi:10.1002/(SICI)1097-0215(19970516)71:4<556::AID-IJC9>3.0.CO;2-T
21.M. Kono, Y. Ohyama, Y. C. Lee, T. Hamamoto, N. Kojima & S. Tsuji: Mouse beta-galactoside alpha 2,3-sialyltransferases: comparison of in vitro substrate specificities and tissue specific expression. Glycobiology, 7, 469-479 (1997)
doi:10.1093/glycob/7.4.469
22.Y. C. Lee, N. Kurosawa, T. Hamamoto, T. Nakaoka & S. Tsuji: Molecular cloning and expression of Gal beta 1,3GalNAc alpha 2,3-sialyltransferase from mouse brain. Eur J Biochem, 216, 377-385 (1993)
doi:10.1111/j.1432-1033.1993.tb18155.x
23.V. Giordanengo, S. Bannwarth, C. Laffont, V. Van Miegem, A. Harduin-Lepers, P. Delannoy & J. C. Lefebvre: Cloning and expression of cDNA for a human Gal(beta1-3)GalNAc alpha2,3-sialyltransferase from the CEM T-cell line. Eur J Biochem, 247, 558-566 (1997)
doi:10.1111/j.1432-1033.1997.00558.x
24.N. Kojima, Y. C. Lee, T. Hamamoto, N. Kurosawa & S. Tsuji: Kinetic properties and acceptor substrate preferences of two kinds of Gal beta 1,3GalNAc alpha 2,3-sialyltransferase from mouse brain. Biochemistry, 33, 5772-5776 (1994)
doi:10.1021/bi00185a014
25.I. Brockhausen, J. M. Yang, J. Burchell, C. Whitehouse & J. Taylor-Papadimitriou: Mechanisms underlying aberrant glycosylation of MUC1 mucin in breast cancer cells. Eur J Biochem, 233, 607-617 (1995)
doi:10.1111/j.1432-1033.1995.607_2.x
26.I. Brockhausen: Mucin-type O-glycans in human colon and breast cancer: glycodynamics and functions. EMBO Rep, 7, 599-604 (2006)
doi:10.1038/sj.embor.7400705
27.J. Burchell, R. Poulsom, A. Hanby, C. Whitehouse, L. Cooper, H. Clausen, D. Miles & J. Taylor-Papadimitriou: An alpha2,3 sialyltransferase (ST3Gal I) is elevated in primary breast carcinomas. Glycobiology, 9, 1307-1311 (1999)
28.G. Picco, S. Julien, I. Brockhausen, R. Beatson, A. Antonopoulos, S. Haslam, U. Mandel, A. Dell, S. Pinder, J. Taylor-Papadimitriou & J. Burchell: Over-expression of ST3Gal-I promotes mammary tumorigenesis. Glycobiology, 20, 1241-1250 (2010)
doi:10.1093/glycob/cwq085
29.P. A. Videira, M. Correia, N. Malagolini, H. J. Crespo, D. Ligeiro, F. M. Calais, H. Trindade & F. Dall'Olio: ST3Gal.I sialyltransferase relevance in bladder cancer tissues and cell lines. BMC Cancer, 9, 357 (2009)
doi:10.1186/1471-2407-9-357
30.P. H. Wang, Y. F. Li, C. M. Juang, Y. R. Lee, H. T. Chao, H. T. Ng, Y. C. Tsai & C. C. Yuan: Expression of sialyltransferase family members in cervix squamous cell carcinoma correlates with lymph node metastasis. Gynecol Oncol, 86, 45-52 (2002)
doi:10.1006/gyno.2002.6714
31.P. H. Wang, W. L. Lee, C. M. Juang, Y. H. Yang, W. H. Lo, C. R. Lai, S. L. Hsieh & C. C. Yuan: Altered mRNA expressions of sialyltransferases in ovarian cancers. Gynecol Oncol, 99, 631-639 (2005)
doi:10.1016/j.ygyno.2005.07.016
32.T. Kudo, Y. Ikehara, A. Togayachi, K. Morozumi, M. Watanabe, M. Nakamura, S. Nishihara & H. Narimatsu: Up-regulation of a set of glycosyltransferase genes in human colorectal cancer. Lab Invest, 78, 797-811 (1998)
33.M. A. Recchi, A. Harduin-Lepers, Y. Boilly-Marer, A. Verbert & P. Delannoy: Multiplex RT-PCR method for the analysis of the expression of human sialyltransferases: application to breast cancer cells. Glycoconj J, 15, 19-27 (1998)
doi:10.1023/A:1006983214918
34.M. A. Recchi, M. Hebbar, L. Hornez, A. Harduin-Lepers, J. P. Peyrat & P. Delannoy: Multiplex reverse transcription polymerase chain reaction assessment of sialyltransferase expression in human breast cancer. Cancer Res, 58, 4066-4070 (1998)
35.H. Kitagawa & J. C. Paulson: Cloning and expression of human Gal beta 1,3(4)GlcNAc alpha 2,3-sialyltransferase. Biochem Biophys Res Commun, 194, 375-382 (1993)
doi:10.1006/bbrc.1993.1830
36.H. Kitagawa & J. C. Paulson: Cloning of a novel alpha 2,3-sialyltransferase that sialylates glycoprotein and glycolipid carbohydrate groups. J Biol Chem, 269, 1394-1401 (1994)
37.T. Okajima, S. Fukumoto, H. Miyazaki, H. Ishida, M. Kiso, K. Furukawa, T. Urano & K. Furukawa: Molecular cloning of a novel alpha2,3-sialyltransferase (ST3Gal VI) that sialylates type II lactosamine structures on glycoproteins and glycolipids. J Biol Chem, 274, 11479-11486 (1999)
doi:10.1074/jbc.274.17.11479
38.K. Sasaki, E. Watanabe, K. Kawashima, S. Sekine, T. Dohi, M. Oshima, N. Hanai, T. Nishi & M. Hasegawa: Expression cloning of a novel Gal beta (1-3/1-4) GlcNAc alpha 2,3-sialyltransferase using lectin resistance selection. J Biol Chem, 268, 22782-22787 (1993)
39.A. S. Carvalho, A. Harduin-Lepers, A. Magalhaes, E. Machado, N. Mendes, L. T. Costa, R. Matthiesen, R. Almeida, J. Costa & C. A. Reis: Differential expression of alpha-2,3-sialyltransferases and alpha-1,3/4-fucosyltransferases regulates the levels of sialyl Lewis a and sialyl Lewis x in gastrointestinal carcinoma cells. Int J Biochem Cell Biol, 42, 80-89 (2010)
doi:10.1016/j.biocel.2009.09.010
40.F. Dall'olio: Protein glycosylation in cancer biology: an overview. Clin Mol Pathol, 49, M126-135 (1996)
doi:10.1136/mp.49.3.M126
41.A. Cazet, S. Julien, M. Bobowski, M. A. Krzewinski-Recchi, A. Harduin-Lepers, S. Groux-Degroote & P. Delannoy: Consequences of the expression of sialylated antigens in breast cancer. Carbohydr Res (2010)
doi:10.1016/j.carres.2010.01.024
42.M. Perez-Garay, B. Arteta, L. Pages, R. de Llorens, C. de Bolos, F. Vidal-Vanaclocha & R. Peracaula: alpha2,3-sialyltransferase ST3Gal III modulates pancreatic cancer cell motility and adhesion in vitro and enhances its metastatic potential in vivo. PLoS One, 5, (2010)
doi:10.1371/journal.pone.0012524
43.A. Ishii, M. Ohta, Y. Watanabe, K. Matsuda, K. Ishiyama, K. Sakoe, M. Nakamura, J. Inokuchi, Y. Sanai & M. Saito: Expression cloning and functional characterization of human cDNA for ganglioside GM3 synthase. J Biol Chem, 273, 31652-31655 (1998)
doi:10.1074/jbc.273.48.31652
44.P. Berselli, S. Zava, E. Sottocornola, S. Milani, B. Berra & I. Colombo: Human GM3 synthase: a new mRNA variant encodes an NH2-terminal extended form of the protein. Biochim Biophys Acta, 1759, 348-358 (2006)
doi:10.1016/j.bbaexp.2006.07.001
45.S. Mondal, S. Chandra & C. Mandal: Elevated mRNA level of hST6Gal I and hST3Gal V positively correlates with the high risk of pediatric acute leukemia. Leuk Res, 34, 463-470 (2010)
doi:10.1016/j.leukres.2009.07.042
46.F. Dall'Olio: The sialyl-alpha2,6-lactosaminyl-structure: biosynthesis and functional role. Glycoconj J, 17, 669-676 (2000)
doi:10.1023/A:1011077000164
47.D. Petit, A. M. Mir, J. M. Petit, C. Thisse, P. Delannoy, R. Oriol, B. Thisse & A. Harduin-Lepers: Molecular phylogeny and functional genomics of {beta}-galactoside {alpha}2,6-sialyltransferases that explain ubiquitous expression of st6gal1 gene in amniotes. J Biol Chem, 285, 38399-38414 (2010)
doi:10.1074/jbc.M110.163931
48.P. F. Rohfritsch, J. A. Joosten, M. A. Krzewinski-Recchi, A. Harduin-Lepers, B. Laporte, S. Juliant, M. Cerutti, P. Delannoy, J. F. Vliegenthart & J. P. Kamerling: Probing the substrate specificity of four different sialyltransferases using synthetic beta-D-Galp-(1-->4)-beta-D-GlcpNAc-(1-->2)-alpha-D-Manp-(1-->O) (CH(2))7CH3 analogues general activating effect of replacing N-acetylglucosamine by N-propionylglucosamine. Biochim Biophys Acta, 1760, 685-692 (2006)
<
doi:10.1016/j.bbagen.2005.12.012
49.H. Korekane, A. Matsumoto, F. Ota, T. Hasegawa, Y. Misonou, K. Shida, Y. Miyamoto & N. Taniguchi: Involvement of ST6Gal I in the biosynthesis of a unique human colon cancer biomarker candidate, alpha2,6-sialylated blood group type 2H (ST2H) antigen. J Biochem, 148, 359-370 (2010)
doi:10.1093/jb/mvq077
50.M. A. Krzewinski-Recchi, S. Julien, S. Juliant, M. Teintenier-Lelievre, B. Samyn-Petit, M. D. Montiel, A. M. Mir, M. Cerutti, A. Harduin-Lepers & P. Delannoy: Identification and functional expression of a second human beta-galactoside alpha2,6-sialyltransferase, ST6Gal II. Eur J Biochem, 270, 950-961 (2003)
doi:10.1046/j.1432-1033.2003.03458.x
50.M. A. Krzewinski-Recchi, S. Julien, S. Juliant, M. Teintenier-Lelievre, B. Samyn-Petit, M. D. Montiel, A. M. Mir, M. Cerutti, A. Harduin-Lepers & P. Delannoy: Identification and functional expression of a second human beta-galactoside alpha2,6-sialyltransferase, ST6Gal II. Eur J Biochem, 270, 950-961 (2003)
doi:10.1046/j.1432-1033.2003.03458.x
51.S. Takashima, S. Tsuji & M. Tsujimoto: Characterization of the second type of human beta-galactoside alpha 2,6-sialyltransferase (ST6Gal II), which sialylates Galbeta 1,4GlcNAc structures on oligosaccharides preferentially. Genomic analysis of human sialyltransferase genes. J Biol Chem, 277, 45719-45728 (2002)
doi:10.1074/jbc.M206808200
52.S. Takashima, S. Tsuji & M. Tsujimoto: Comparison of the enzymatic properties of mouse beta-galactoside alpha2,6-sialyltransferases, ST6Gal I and II. J Biochem, 134, 287-296 (2003)
doi:10.1093/jb/mvg142
53.F. Dall'Olio, N. Malagolini, G. Di Stefano, M. Ciambella & F. Serafini-Cessi: Alpha 2,6 sialylation of N-acetyllactosaminic sequences in human colorectal cancer cell lines. Relationship with non-adherent growth. Int J Cancer, 47, 291-297 (1991)
doi:10.1002/ijc.2910470220
54.F. Dall'Olio, N. Malagolini & F. Serafini-Cessi: The expression of soluble and cell-bound alpha 2,6 sialyltransferase in human colonic carcinoma CaCo-2 cells correlates with the degree of enterocytic differentiation. Biochem Biophys Res Commun, 184, 1405-1410 (1992)
doi:10.1016/S0006-291X(05)80039-7
55.P. Gessner, S. Riedl, A. Quentmaier & W. Kemmner: Enhanced activity of CMP-neuAc:Gal beta 1-4GlcNAc:alpha 2,6-sialyltransferase in metastasizing human colorectal tumor tissue and serum of tumor patients. Cancer Lett, 75, 143-149 (1993)
doi:10.1016/0304-3835(93)90056-F
56.T. Petretti, W. Kemmner, B. Schulze & P. M. Schlag: Altered mRNA expression of glycosyltransferases in human colorectal carcinomas and liver metastases. Gut, 46, 359-366 (2000)
doi:10.1136/gut.46.3.359
57.P. O. Skacel, A. J. Edwards, C. T. Harrison & W. M. Watkins: Enzymic control of the expression of the X determinant (CD15) in human myeloid cells during maturation: the regulatory role of 6-sialytransferase. Blood, 78, 1452-1460 (1991)
58.K. Fukushima, S. Hara-Kuge, A. Seko, Y. Ikehara & K. Yamashita: Elevation of alpha2-->6 sialyltransferase and alpha1-->2 fucosyltransferase activities in human choriocarcinoma. Cancer Res, 58, 4301-4306 (1998)
59.Y. Kaneko, H. Yamamoto, D. S. Kersey, K. J. Colley, J. E. Leestma & J. R. Moskal: The expression of Gal beta 1,4GlcNAc alpha 2,6 sialyltransferase and alpha 2,6-linked sialoglycoconjugates in human brain tumors. Acta Neuropathol, 91, 284-292 (1996)
doi:10.1007/s004010050427
60.P. H. Wang, Y. F. Li, C. M. Juang, Y. R. Lee, H. T. Chao, Y. C. Tsai & C. C. Yuan: Altered mRNA expression of sialyltransferase in squamous cell carcinomas of the cervix. Gynecol Oncol, 83, 121-127 (2001)
doi:10.1006/gyno.2001.6358
61.M. Hedlund, E. Ng, A. Varki & N. M. Varki: alpha 2-6-Linked sialic acids on N-glycans modulate carcinoma differentiation in vivo. Cancer Res, 68, 388-394 (2008)
doi:10.1158/0008-5472.CAN-07-1340
62.Y. Ikehara, N. Kojima, N. Kurosawa, T. Kudo, M. Kono, S. Nishihara, S. Issiki, K. Morozumi, S. Itzkowitz, T. Tsuda, S. I. Nishimura, S. Tsuji & H. Narimatsu: Cloning and expression of a human gene encoding an N-acetylgalactosamine-alpha2,6-sialyltransferase (ST6GalNAc I): a candidate for synthesis of cancer-associated sialyl-Tn antigens. Glycobiology, 9, 1213-1224 (1999)
doi:10.1093/glycob/9.11.1213
63.B. Samyn-Petit, M. A. Krzewinski-Recchi, W. F. Steelant, P. Delannoy & A. Harduin-Lepers: Molecular cloning and functional expression of human ST6GalNAc II. Molecular expression in various human cultured cells. Biochim Biophys Acta, 1474, 201-211 (2000)
doi:10.1016/S0304-4165(00)00020-9
64.T. Kjeldsen, H. Clausen, S. Hirohashi, T. Ogawa, H. Iijima & S. Hakomori: Preparation and characterization of monoclonal antibodies directed to the tumor-associated O-linked sialosyl-2----6 alpha-N-acetylgalactosaminyl (sialosyl-Tn) epitope. Cancer Res, 48, 2214-2220 (1988)
65.N. T. Marcos, S. Pinho, C. Grandela, A. Cruz, B. Samyn-Petit, A. Harduin-Lepers, R. Almeida, F. Silva, V. Morais, J. Costa, J. Kihlberg, H. Clausen & C. A. Reis: Role of the human ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancer-associated sialyl-Tn antigen. Cancer Res, 64, 7050-7057 (2004)
doi:10.1158/0008-5472.CAN-04-1921
66.C. Vazquez-Martin, E. Cuevas, E. Gil-Martin & A. Fernandez-Briera: Correlation analysis between tumor-associated antigen sialyl-Tn expression and ST6GalNAc I activity in human colon adenocarcinoma. Oncology, 67, 159-165 (2004)
doi:10.1159/000081003
67.S. Pinho, N. T. Marcos, B. Ferreira, A. S. Carvalho, M. J. Oliveira, F. Santos-Silva, A. Harduin-Lepers & C. A. Reis: Biological significance of cancer-associated sialyl-Tn antigen: modulation of malignant phenotype in gastric carcinoma cells. Cancer Lett, 249, 157-170 (2007)
doi:10.1016/j.canlet.2006.08.010
68.A. Harduin-Lepers, D. C. Stokes, W. F. Steelant, B. Samyn-Petit, M. A. Krzewinski-Recchi, V. Vallejo-Ruiz, J. P. Zanetta, C. Auge & P. Delannoy: Cloning, expression and gene organization of a human Neu5Ac alpha 2-3Gal beta 1-3GalNAc alpha 2,6-sialyltransferase: hST6GalNAcIV. Biochem J, 352 Pt 1, 37-48 (2000)
doi:10.1042/0264-6021:3520037
69.A. Tsuchida, M. Ogiso, Y. Nakamura, M. Kiso, K. Furukawa & K. Furukawa: Molecular cloning and expression of human ST6GalNAc III: restricted tissue distribution and substrate specificity. J Biochem, 138, 237-243 (2005)
doi:10.1093/jb/mvi124
70.A. Tsuchida, T. Okajima, K. Furukawa, T. Ando, H. Ishida, A. Yoshida, Y. Nakamura, R. Kannagi, M. Kiso & K. Furukawa: Synthesis of disialyl Lewis a (Le(a)) structure in colon cancer cell lines by a sialyltransferase, ST6GalNAc VI, responsible for the synthesis of alpha-series gangliosides. J Biol Chem, 278, 22787-22794 (2003)
doi:10.1074/jbc.M211034200
71.M. Senda, A. Ito, A. Tsuchida, T. Hagiwara, T. Kaneda, Y. Nakamura, K. Kasama, M. Kiso, K. Yoshikawa, Y. Katagiri, Y. Ono, M. Ogiso, T. Urano, K. Furukawa, S. Oshima & K. Furukawa: Identification and expression of a sialyltransferase responsible for the synthesis of disialylgalactosylgloboside in normal and malignant kidney cells: downregulation of ST6GalNAc VI in renal cancers. Biochem J, 402, 459-470 (2007)
doi:10.1042/BJ20061118
72.P. D. Bos, X. H. Zhang, C. Nadal, W. Shu, R. R. Gomis, D. X. Nguyen, A. J. Minn, M. J. van de Vijver, W. L. Gerald, J. A. Foekens & J. Massague: Genes that mediate breast cancer metastasis to the brain. Nature, 459, 1005-1009 (2009)
doi:10.1038/nature08021
73.R. A. Kroes, H. He, M. R. Emmett, C. L. Nilsson, F. E. Leach, 3rd, I. J. Amster, A. G. Marshall & J. R. Moskal: Overexpression of ST6GalNAcV, a ganglioside-specific alpha2,6-sialyltransferase, inhibits glioma growth in vivo. Proc Natl Acad Sci U S A, 107, 12646-12651 (2010)
doi:10.1073/pnas.0909862107
74.K. Miyazaki, K. Ohmori, M. Izawa, T. Koike, K. Kumamoto, K. Furukawa, T. Ando, M. Kiso, T. Yamaji, Y. Hashimoto, A. Suzuki, A. Yoshida, M. Takeuchi & R. Kannagi: Loss of disialyl Lewis(a), the ligand for lymphocyte inhibitory receptor sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7) associated with increased sialyl Lewis(a) expression on human colon cancers. Cancer Res, 64, 4498-4505 (2004)
doi:10.1158/0008-5472.CAN-03-3614
75.K. Nara, Y. Watanabe, K. Maruyama, K. Kasahara, Y. Nagai & Y. Sanai: Expression cloning of a CMP-NeuAc: NeuAca2-3Galb1-4Glcb1-1'Cer a2,8-sialyltransferase (GD3 synthase) from human melanoma cells. Proc Natl Acad Sci U S A, 91, 7952-7956 (1994)
doi:10.1073/pnas.91.17.7952
76.J. Nakayama, M. N. Fukuda, Y. Hirabayashi, A. Kanamori, K. Sasaki, T. Nishi & M. Fukuda: Expression cloning of a human GT3 synthase. GD3 and GT3 are synthesized by a single enzyme. J Biol Chem, 271, 3684-3691 (1996)
doi: 10.1074/jbc.271.7.3684
77.Y. J. Kim, K. S. Kim, S. Do, C. H. Kim, S. K. Kim & Y. C. Lee: Molecular cloning and expression of human alpha2,8-sialyltransferase (hST8Sia V). Biochem Biophys Res Commun, 235, 327-330 (1997)
doi:10.1006/bbrc.1997.6725
78.RK Yu, E Bieberich, T Xia & G Zeng: Regulation of ganglioside biosynthesis in the nervous system. J Lipid Res., 45, 783-793 (2004)
doi:10.1194/jlr.R300020-JLR200
79.M. Teintenier-Lelievre, S. Julien, S. Juliant, Y. Guerardel, M. Duonor-Cerutti, P. Delannoy & A. Harduin-Lepers: Molecular cloning and expression of a human hST8Sia VI (a2,8-sialyltransferase) responsible for the synthesis of the diSia motif on O-glycosylproteins. Biochem J, 392, 665-674 (2005)
doi: 10.1042/BJ20051120
80.A. Rohrbeck, V. S. Muller & J. Borlak: Molecular characterization of lung dysplasia induced by c-Raf-1. PLoS One, 4, e5637 (2009)
doi: 10.1371/journal.pone.0005637
81.Y. C. Lee, Y. J. Kim, K. Y. Lee, K. S. Kim, B. U. Kim, H. N. Kim, C. H. Kim & S. I. Do: Cloning and expression of cDNA for a human Sia alpha 2,3Gal beta 1, 4GlcNA:alpha 2,8-sialyltransferase (hST8Sia III). Arch Biochem Biophys, 360, 41-46 (1998)
doi:10.1006/abbi.1998.0909
82.R. K. Yu, L. J. Macala, T. Taki, H. M. Weinfield & F. S. Yu: Developmental changes in ganglioside composition and synthesis in embryonic rat brain. J Neurochem, 50, 1825-1829 (1988)
doi:10.1111/j.1471-4159.1988.tb02484.x
83.E. Inoko, Y. Nishiura, H. Tanaka, T. Takahashi, K. Furukawa, K. Kitajima & C. Sato: Developmental stage-dependent expression of an alpha2,8-trisialic acid unit on glycoproteins in mouse brain. Glycobiology, 20, 916-928 (2010)
doi:10.1093/glycob/cwq049
84.K. Angata, M. Suzuki, J. McAuliffe, Y. Ding, O. Hindsgaul & M. Fukuda: Differential biosynthesis of polysialic acid on neural cell adhesion molecule (NCAM) and oligosaccharide acceptors by three distinct alpha 2,8-sialyltransferases, ST8Sia IV (PST), ST8Sia II (STX), and ST8Sia III. J Biol Chem, 275, 18594-18601 (2000)
doi:10.1074/jbc.M910204199
85.C. Sato, T. Matsuda & K. Kitajima: Neuronal differentiation-dependent expression of the disialic acid epitope on CD166 and its involvement in neurite formation in Neuro2A cells. J Biol Chem, 277, 45299-45305 (2002)
doi:10.1074/jbc.M206046200
86.N. Kojima, Y. Yoshida & S. Tsuji: A developmentally regulated member of the sialyltransferase family (ST8Sia II, STX) is a polysialic acid synthase. FEBS Lett, 373, 119-122 (1995)
doi:10.1016/0014-5793(95)01024-9
87.J. Nakayama, M. N. Fukuda, B. Fredette, B. Ranscht & M. Fukuda: Expression cloning of a human polysialyltransferase that forms the polysialylated neural cell adhesion molecule present in embryonic brain. Proc Natl Acad Sci U S A, 92, 7031-7035 (1995)
doi:10.1073/pnas.92.15.7031
88.E. P. Scheidegger, L. R. Sternberg, J. Roth & J. B. Lowe: A human STX cDNA confers polysialic acid expression in mammalian cells. J Biol Chem, 270, 22685-22688 (1995)
doi:10.1074/jbc.270.39.22685
89.N. Kojima, Y. Tachida, Y. Yoshida & S. Tsuji: Characterization of mouse ST8Sia II (STX) as a neural cell adhesion molecule-specific polysialic acid synthase. Requirement of core alpha1,6-linked fucose and a polypeptide chain for polysialylation. J Biol Chem, 271, 19457-19463 (1996)
doi:10.1074/jbc.271.32.19457
90.M. Muhlenhoff, M. Eckhardt, A. Bethe, M. Frosch & R. Gerardy-Schahn: Polysialylation of NCAM by a single enzyme. Curr Biol, 6, 1188-1191 (1996)
doi:10.1016/S0960-9822(02)70687-8
91.J. Nakayama, K. Angata, E. Ong, T. Katsuyama & M. Fukuda: Polysialic acid, a unique glycan that is developmentally regulated by two polysialyltransferases, PST and STX, in the central nervous system: from biosynthesis to function. Pathol Int, 48, 665-677 (1998)
doi:10.1111/j.1440-1827.1998.tb03967.x
92.H. Hildebrandt, M. Muhlenhoff, B. Weinhold & R. Gerardy-Schahn: Dissecting polysialic acid and NCAM functions in brain development. J Neurochem, 103 Suppl 1, 56-64 (2007)
doi:10.1111/j.1471-4159.2007.04716.x
93.Y. Matsushita, S. Yonezawa, S. Nakamori, T. Irimura & E. Sato: Carbohydrate antigens aberrantly expressed in colorectal carcinoma. Crit Rev Oncol Hematol, 25, 27-54 (1997)
doi:10.1016/S1040-8428(96)00227-2
94.A. Imberty, C. Gautier, J. Lescar, S. Perez, L. Wyns & R. Loris: An unusual carbohydrate binding site revealed by the structures of two Maackia amurensis lectins complexed with sialic acid-containing oligosaccharides. J Biol Chem, 275, 17541-17548 (2000)
doi:10.1074/jbc.M000560200
95.S. Kurachi, Z. Song, M. Takagaki, Q. Yang, H. C. Winter, K. Kurachi & I. J. Goldstein: Sialic-acid-binding lectin from the slug Limax flavus--cloning, expression of the polypeptide, and tissue localization. Eur J Biochem, 254, 217-222 (1998)
doi:10.1046/j.1432-1327.1998.2540217.x
96.F. Y. Zeng & H. J. Gabius: Sialic acid-binding proteins: characterization, biological function and application. Z Naturforsch C, 47, 641-653 (1992)
97.P. de Albuquerque Garcia Redondo, C. V. Nakamura, W. de Souza & J. A. Morgado-Diaz: Differential expression of sialic acid and N-acetylgalactosamine residues on the cell surface of intestinal epithelial cells according to normal or metastatic potential. J Histochem Cytochem, 52, 629-640 (2004)
98.Y. Shio, H. Suzuki, T. Kawaguchi, J. Ohsugi, M. Higuchi, K. Fujiu, R. Kanno, A. Ohishi & M. Gotoh: Carbohydrate status detecting by PNA is changeable through cancer prognosis from primary to metastatic nodal site: A possible prognostic factor in patient with node-positive lung adenocarcinoma. Lung Cancer, 57, 187-192 (2007)
99.L. Johansson, P. Johansson & H. Miller-Podraza: Detection by the lectins from Maackia amurensis and Sambucus nigra of 3- and 6-linked sialic acid in gangliosides with neolacto chains separated on thin-layer chromatograms and blotted to PVDF membranes. Anal Biochem, 267, 239-241 (1999)
doi:10.1006/abio.1998.2982
100.G. Harms, G. Reuter, A. P. Corfield & R. Schauer: Binding specificity of influenza C-virus to variably O-acetylated glycoconjugates and its use for histochemical detection of N-acetyl-9-O-acetylneuraminic acid in mammalian tissues. Glycoconj J, 13, 621-630 (1996)
doi:10.1007/BF00731450
101.R. Kannagi: Carbohydrate antigen sialyl Lewis a--its pathophysiological significance and induction mechanism in cancer progression. Chang Gung Med J, 30, 189-209 (2007)
102.R. L. Schnaar, P. Longo, L. J. Yang & T. Tai: Distinctive ganglioside patterns revealed by anti-ganglioside antibody binding to differentiating CG-4 oligodendrocytes. Glycobiology, 6, 257-263 (1996)
doi:10.1093/glycob/6.3.257
103.C. S. Pukel, K. O. Lloyd, L. R. Travassos, W. G. Dippold, H. F. Oettgen & L. J. Old: GD3, a prominent ganglioside of human melanoma. Detection and characterisation by mouse monoclonal antibody. J Exp Med, 155, 1133-1147 (1982)
doi:10.1084/jem.155.4.1133
104.G. Marquina, H. Waki, L. E. Fernandez, K. Kon, A. Carr, O. Valiente, R. Perez & S. Ando: Gangliosides expressed in human breast cancer. Cancer Res, 56, 5165-5171 (1996)
105.C. Costa-Nogueira, S. Villar-Portela, E. Cuevas, E. Gil-Martin & A. Fernandez-Briera: Synthesis and expression of CDw75 antigen in human colorectal cancer. BMC Cancer, 9, 431 (2009)
doi:10.1186/1471-2407-9-431
106.S. Gretschel, W. Haensch, P. M. Schlag & W. Kemmner: Clinical relevance of sialyltransferases ST6GAL-I and ST3GAL-III in gastric cancer. Oncology, 65, 139-145 (2003)
doi:10.1159/000072339
107.A. Harduin-Lepers, D. Petit, R. Mollicone, P. Delannoy, J. M. Petit & R. Oriol: Evolutionary history of the alpha2,8-sialyltransferase (ST8Sia) gene family: tandem duplications in early deuterostomes explain most of the diversity found in the vertebrate ST8Sia genes. BMC Evol Biol, 8, 258 (2008)
doi:10.1186/1471-2148-8-258
108.M. Hebbar, M. A. Krzewinski-Recchi, L. Hornez, A. Verdiere, A. Harduin-Lepers, J. Bonneterre, P. Delannoy & J. P. Peyrat: Prognostic value of tumoral sialyltransferase expression and circulating E-selectin concentrations in node-negative breast cancer patients. Int J Biol Markers, 18, 116-122 (2003)
109.I. Y. Cheung, A. Vickers & N. K. Cheung: Sialyltransferase STX (ST8SiaII): a novel molecular marker of metastatic neuroblastoma. Int J Cancer, 119, 152-156 (2006)
doi:10.1002/ijc.21789
110.N. Patani, W. Jiang & K. Mokbel: Prognostic utility of glycosyltransferase expression in breast cancer. Cancer Genomics Proteomics, 5, 333-340 (2008)
111.F. Fialka, R. M. Gruber, R. Hitt, L. Opitz, E. Brunner, H. Schliephake & F. J. Kramer: CPA6, FMO2, LGI1, SIAT1 and TNC are differentially expressed in early- and late-stage oral squamous cell carcinoma--a pilot study. Oral Oncol, 44, 941-948 (2008)
doi:10.1016/j.oraloncology.2007.10.011
112.E. Ruckhaberle, T. Karn, A. Rody, L. Hanker, R. Gatje, D. Metzler, U. Holtrich & M. Kaufmann: Gene expression of ceramide kinase, galactosyl ceramide synthase and ganglioside GD3 synthase is associated with prognosis in breast cancer. J Cancer Res Clin Oncol, 135, 1005-1013 (2009)
doi:10.1007/s00432-008-0536-6
113.W. Kemmner, C. Roefzaad, W. Haensch & P. M. Schlag: Glycosyltransferase expression in human colonic tissue examined by oligonucleotide arrays. Biochim Biophys Acta, 1621, 272-279 (2003)
doi:10.1016/S0304-4165(03)00079-5
114.R. A. Kroes, G. Dawson & J. R. Moskal: Focused microarray analysis of glyco-gene expression in human glioblastomas. J Neurochem, 103 Suppl 1, 14-24 (2007)
doi:10.1111/j.1471-4159.2007.04780.x
115.C. Y. Wu, C. C. Hsu, S. T. Chen & Y. C. Tsai: Soyasaponin I, a potent and specific sialyltransferase inhibitor. Biochem Biophys Res Commun, 284, 466-469 (2001)
doi:10.1006/bbrc.2001.5002
116.D. Skropeta, R. Schworer, T. Haag & R. R. Schmidt: Asymmetric synthesis and affinity of potent sialyltransferase inhibitors based on transition-state analogues. Glycoconj J, 21, 205-219 (2004)
doi:10.1023/B:GLYC.0000045093.96413.62
117.L. J. Whalen, K. A. McEvoy & R. L. Halcomb: Synthesis and evaluation of phosphoramidate amino acid-based inhibitors of sialyltransferases. Bioorg Med Chem Lett, 13, 301-304 (2003)
doi:10.1016/S0960-894X(02)00735-7
118.X. Wang, L. H. Zhang & X. S. Ye: Recent development in the design of sialyltransferase inhibitors. Med Res Rev, 23, 32-47 (2003)
doi:10.1002/med.10030
119.K. Y. Lee, H. G. Kim, M. R. Hwang, J. I. Chae, J. M. Yang, Y. C. Lee, Y. K. Choo, Y. I. Lee, S. S. Lee & S. I. Do: The Hexapeptide inhibitor of Galbeta 1,3GalNAc-specific alpha 2,3-sialyltransferase as a generic inhibitor of sialyltransferases. J Biol Chem, 277, 49341-49351 (2002)
doi:10.1074/jbc.M209618200
120.A. K. Sarkar, T. A. Fritz, W. H. Taylor & J. D. Esko: Disaccharide uptake and priming in animal cells: inhibition of sialyl Lewis X by acetylated Gal beta 1-->4GlcNAc beta-O-naphthalenemethanol. Proc Natl Acad Sci U S A, 92, 3323-3327 (1995)
121.I. Kijima-Suda, Y. Miyamoto, S. Toyoshima, M. Itoh & T. Osawa: Inhibition of experimental pulmonary metastasis of mouse colon adenocarcinoma 26 sublines by a sialic acid:nucleoside conjugate having sialyltransferase inhibiting activity. Cancer Res, 46, 858-862 (1986)
122.I. Kijima-Suda, T. Miyazawa, M. Itoh, S. Toyoshima & T. Osawa: Possible mechanism of inhibition of experimental pulmonary metastasis of mouse colon adenocarcinoma 26 sublines by a sialic acid: nucleoside conjugate. Cancer Res, 48, 3728-3732 (1988)
123.K. H. Chang, L. Lee, J. Chen & W. S. Li: Lithocholic acid analogues, new and potent alpha-2,3-sialyltransferase inhibitors. Chem Commun (Camb)629-631 (2006)
doi:10.1039/b514915k
124.C. H. Chiang, C. H. Wang, H. C. Chang, S. V. More, W. S. Li & W. C. Hung: A novel sialyltransferase inhibitor AL10 suppresses invasion and metastasis of lung cancer cells by inhibiting integrin-mediated signaling. J Cell Physiol, 223, 492-499 (2010)
doi:10.1002/jcp.22068
125.J. Y. Chen, Y. A. Tang, S. M. Huang, H. F. Juan, L. W. Wu, Y. C. Sun, S. C. Wang, K. W. Wu, G. Balraj, T. T. Chang, W. S. Li, H. C. Cheng & Y. C. Wang: A Novel Sialyltransferase Inhibitor Suppresses FAK/Paxillin Signaling and Cancer Angiogenesis and Metastasis Pathways. Cancer Res, 71, 473-483 (2011)
doi:10.1158/0008-5472.CAN-10-1303
126.P. Delannoy, I. Kim, N. Emery, C. De Bolos, A. Verbert, P. Degand & G. Huet: Benzyl-N-acetyl-alpha-D-galactosaminide inhibits the sialylation and the secretion of mucins by a mucin secreting HT-29 cell subpopulation. Glycoconj J, 13, 717-726 (1996)
doi:10.1007/BF00702335
127.T. Nakano, T. Matsui & T. Ota: Benzyl-alpha-GalNAc inhibits sialylation of O-glycosidic sugar chains on CD44 and enhances experimental metastatic capacity in B16BL6 melanoma cells. Anticancer Res, 16, 3577-3584 (1996)
128.G. Zeng, L. Gao, S. Birkle & R. K. Yu: Suppression of ganglioside GD3 expression in a rat F-11 tumor cell line reduces tumor growth, angiogenesis, and vascular endothelial growth factor production. Cancer Res, 60, 6670-6676 (2000)
129.G. Zeng, D. D. Li, L. Gao, S. Birkle, E. Bieberich, A. Tokuda & R. K. Yu: Alteration of ganglioside composition by stable transfection with antisense vectors against GD3-synthase gene expression. Biochemistry, 38, 8762-8769 (1999)
doi:10.1021/bi9906726
130.S. Birkle, L. Gao, G. Zeng & R. K. Yu: Down-regulation of GD3 ganglioside and its O-acetylated derivative by stable transfection with antisense vector against GD3-synthase gene expression in hamster melanoma cells: effects on cellular growth, melanogenesis, and dendricity. J Neurochem, 74, 547-554 (2000)
131.K. Ko, K. Furukawa, T. Takahashi, T. Urano, Y. Sanai, M. Nagino, Y. Nimura & K. Furukawa: Fundamental study of small interfering RNAs for ganglioside GD3 synthase gene as a therapeutic target of lung cancers. Oncogene, 25, 6924-6935 (2006)
doi:10.1038/sj.onc.1209683
132.Y. Gu, J. Zhang, W. Mi, J. Yang, F. Han, X. Lu & W. Yu: Silencing of GM3 synthase suppresses lung metastasis of murine breast cancer cells. Breast Cancer Res, 10, R1 (2008)
doi:10.1186/bcr1841
133.S. Lin, W. Kemmner, S. Grigull & P. M. Schlag: Cell surface alpha 2,6 sialylation affects adhesion of breast carcinoma cells. Exp Cell Res, 276, 101-110 (2002)
doi:10.1006/excr.2002.5521
134.Y. Zhu, U. Srivatana, A. Ullah, H. Gagneja, C. S. Berenson & P. Lance: Suppression of a sialyltransferase by antisense DNA reduces invasiveness of human colon cancer cells in vitro. Biochim Biophys Acta, 1536, 148-160 (2001)
doi:10.1016/S0925-4439(01)00044-8
135.A. V. Nairn, W. S. York, K. Harris, E. M. Hall, J. M. Pierce & K. W. Moremen: Regulation of glycan structures in animal tissues: transcript profiling of glycan-related genes. J Biol Chem, 283, 17298-17313 (2008)
doi:10.1074/jbc.M801964200
136.A Taniguchi: Promoter structure and transcriptional regulation of human β-galactoside α2,3-sialyltransferase genes. Current Drug Targets, 9, 310-316 (2008)
137.I. Kalcheva, R. W. Elliott, M. Dalziel & J. T. Lau: The gene encoding beta-galactoside alpha2,6-sialyltransferase maps to mouse chromosome 16. Mamm Genome, 8, 619-620 (1997) doi:10.1007/s003359900518
138.D. Mercier, A. Wierinckx, A. Oulmouden, P. F. Gallet, M. M. Palcic, A. Harduin-Lepers, P. Delannoy, J. M. Petit, H. Leveziel & R. Julien: Molecular cloning, expression and exon/intron organization of the bovine beta-galactoside alpha2,6-sialyltransferase gene. Glycobiology, 9, 851-863 (1999)
doi:10.1093/glycob/9.9.851
139.X. Wang, A. Vertino, R. L. Eddy, M. G. Byers, S. N. Jani-Sait, T. B. Shows & J. T. Lau: Chromosome mapping and organization of the human beta-galactoside alpha 2,6-sialyltransferase gene. Differential and cell-type specific usage of upstream exon sequences in B-lymphoblastoid cells. J Biol Chem, 268, 4355-4361 (1993)
140.D. X. Wen, E. C. Svensson & J. C. Paulson: Tissue-specific alternative splicing of the beta-galactoside alpha 2,6-sialyltransferase gene. J Biol Chem, 267, 2512-2518 (1992)
141.F. Dall'Olio, M. Chiricolo, C. Ceccarelli, F. Minni, D. Marrano & D. Santini: Beta-galactoside alpha2,6 sialyltransferase in human colon cancer: contribution of multiple transcripts to regulation of enzyme activity and reactivity with Sambucus nigra agglutinin. Int J Cancer, 88, 58-65 (2000)
doi:10.1002/1097-0215(20001001)88:1<58::AID-IJC9>3.0.CO;2-Q
142.L. Xu, Y. Kurusu, K. Takizawa, J. Tanaka, K. Matsumoto & A. Taniguchi: Transcriptional regulation of human beta-galactoside alpha2,6-sialyltransferase (hST6Gal I) gene in colon adenocarcinoma cell line. Biochem Biophys Res Commun, 307, 1070-1074 (2003)
doi:10.1016/S0006-291X(03)01314-7
143.R. Eskinazi, B. Thony, M. Svoboda, P. Robberecht, D. Dassesse, C. W. Heizmann, J. L. Van Laethem & A. Resibois: Overexpression of pterin-4a-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 in human colon cancer. Am J Pathol, 155, 1105-1113 (1999)
144.P. H. Wang, W. L. Lee, Y. R. Lee, C. M. Juang, Y. J. Chen, H. T. Chao, Y. C. Tsai & C. C. Yuan: Enhanced expression of alpha 2,6-sialyltransferase ST6Gal I in cervical squamous cell carcinoma. Gynecol Oncol, 89, 395-401 (2003)
doi:10.1016/S0090-8258(03)00127-6
145.H. M. Dae, H. Y. Kwon, N. Y. Kang, N. R. Song, K. S. Kim, C. H. Kim, J. H. Lee & Y. C. Lee: Isolation and functional analysis of the human glioblastoma-specific promoter region of the human GD3 synthase (hST8Sia I) gene. Acta Biochim Biophys Sin (Shanghai), 41, 237-245 (2009)
doi:10.1093/abbs/gmp007
146.K. Furukawa, M. Horie, K. Okutomi, S. Sugano & K. Furukawa: Isolation and functional analysis of the melanoma specific promoter region of human GD3 synthase gene. Biochim Biophys Acta, 1627, 71-78 (2003)
doi:10.1016/S0167-4781(03)00076-9
147.N. Y. Kang, C. H. Kim, K. S. Kim, J. H. Ko, J. H. Lee, Y. K. Jeong & Y. C. Lee: Expression of the human CMP-NeuAc:GM3 alpha2,8-sialyltransferase (GD3 synthase) gene through the NF-kappaB activation in human melanoma SK-MEL-2 cells. Biochim Biophys Acta, 1769, 622-630 (2007)
doi:10.1016/j.bbaexp.2007.08.001
148.J. M. Yang, J. C. Byrd, B. B. Siddiki, Y. S. Chung, M. Okuno, M. Sowa, Y. S. Kim, K. L. Matta & I. Brockhausen: Alterations of O-glycan biosynthesis in human colon cancer tissues. Glycobiology, 4, 873-884 (1994)
doi:10.1093/glycob/4.6.873
149.F. G. Hanisch, T. R. Stadie, F. Deutzmann & J. Peter-Katalinic: MUC1 glycoforms in breast cancer--cell line T47D as a model for carcinoma-associated alterations of 0-glycosylation. Eur J Biochem, 236, 318-327 (1996)
doi:10.1111/j.1432-1033.1996.00318.x
150.K. O. Lloyd, J. Burchell, V. Kudryashov, B. W. Yin & J. Taylor-Papadimitriou: Comparison of O-linked carbohydrate chains in MUC-1 mucin from normal breast epithelial cell lines and breast carcinoma cell lines. Demonstration of simpler and fewer glycan chains in tumor cells. J Biol Chem, 271, 33325-33334 (1996)
151.J. Taylor-Papadimitriou, J. Burchell, D. W. Miles & M. Dalziel: MUC1 and cancer. Biochim Biophys Acta, 1455, 301-313 (1999)
doi:10.1016/S0925-4439(99)00055-1
152.S. Muller & F. G. Hanisch: Recombinant MUC1 probe authentically reflects cell-specific O-glycosylation profiles of endogenous breast cancer mucin. High density and prevalent core 2-based glycosylation. J Biol Chem, 277, 26103-26112 (2002)
doi:10.1074/jbc.M202921200
153.K. Sebova & I. Fridrichova: Epigenetic tools in potential anticancer therapy. Anticancer Drugs, 21, 565-577 (2010)
doi:10.1097/CAD.0b013e32833a4352
154.R. Kannagi, J. Yin, K. Miyazaki & M. Izawa: Current relevance of incomplete synthesis and neo-synthesis for cancer-associated alteration of carbohydrate determinants--Hakomori's concepts revisited. Biochim Biophys Acta, 1780, 525-531 (2008)
doi:10.1016/j.bbagen.2007.10.007
155.Y. I. Kawamura, M. Toyota, R. Kawashima, T. Hagiwara, H. Suzuki, K. Imai, Y. Shinomura, T. Tokino, R. Kannagi & T. Dohi: DNA hypermethylation contributes to incomplete synthesis of carbohydrate determinants in gastrointestinal cancer. Gastroenterology, 135, 142-151 e143 (2008)
doi:10.1053/j.gastro.2008.03.031
156.V. B. Chachadi, H. Cheng, D. Klinkebiel, J. K. Christman & P. W. Cheng: 5-Aza-2'-deoxycytidine increases sialyl Lewis X on MUC1 by stimulating beta-galactoside:alpha2,3-sialyltransferase 6 gene. Int J Biochem Cell Biol (2011)
doi:10.1016/j.biocel.2010.12.015
157.C. D. Margetts, M. Morris, D. Astuti, D. C. Gentle, A. Cascon, F. E. McRonald, D. Catchpoole, M. Robledo, H. P. Neumann, F. Latif & E. R. Maher: Evaluation of a functional epigenetic approach to identify promoter region methylation in phaeochromocytoma and neuroblastoma. Endocr Relat Cancer, 15, 777-786 (2008)
doi:10.1677/ERC-08-0072
158.A. Harduin-Lepers, M. A. Krzewinski-Recchi, M. Hebbar, B. Samyn-Petit, V. Vallejo-Ruiz, S. Julien, J.P. Peyrat & P. Delannoy: Sialyltransferases and breast cancer. Recent Res. Devel. Cancer, 3, 111-126 (2001)
159.J. Ma, M. Simonovic, R. Qian & K. J. Colley: Sialyltransferase isoforms are phosphorylated in the cis-medial Golgi on serine and threonine residues in their luminal sequences. J Biol Chem, 274, 8046-8052 (1999)
doi:10.1074/jbc.274.12.8046
160.K. C. Breen & N. Georgopoulou: The role of protein phosphorylation in alpha2,6(N)-sialyltransferase activity. Biochem Biophys Res Commun, 309, 32-35 (2003)
doi:10.1016/S0006-291X(03)01529-8
161.E. Bieberich, B. Freischutz, S. S. Liour & R. K. Yu: Regulation of ganglioside metabolism by phosphorylation and dephosphorylation. J Neurochem, 71, 972-979 (1998)
doi:10.1046/j.1471-4159.1998.71030972.x
162.D. Skropeta: The effect of individual N-glycans on enzyme activity. Bioorg Med Chem, 17, 2645-2653 (2009)
doi:10.1016/j.bmc.2009.02.037
163.P. Broquet, P. George, J. Geoffroy, P. Reboul & P. Louisot: Study of O-glycan sialylation in C6 cultured glioma cells: evidence for post-translational regulation of a beta-galactoside alpha 2,3 sialyltransferase activity by N-glycosylation. Biochem Biophys Res Commun, 178, 1437-1443 (1991)
doi:10.1016/0006-291X(91)91054-G
164.C. Chen & K. J. Colley: Minimal structural and glycosylation requirements for ST6Gal I activity and trafficking. Glycobiology, 10, 531-583 (2000)
doi:10.1093/glycob/10.5.531
165.E. Bieberich, T. Tencomnao, D. Kapitonov & R. K. Yu: Effect of N-glycosylation on turnover and subcellular distribution of N-acetylgalactosaminyltransferase I and sialyltransferase II in neuroblastoma cells. J Neurochem, 74, 2359-2364 (2000)
doi:10.1046/j.1471-4159.2000.0742359.x
166.C. Jeanneau, V. Chazalet, C. Auge, D. M. Soumpasis, A. Harduin-Lepers, P. Delannoy, A. Imberty & C. Breton: Structure-function analysis of the human sialyltransferase ST3Gal I: role of N-glycosylation and a novel conserved sialylmotif. J Biol Chem, 279, 13461-13468 (2004)
doi:10.1074/jbc.M311764200
167.D. G. Fast, J. C. Jamieson & G. McCaffrey: The role of the carbohydrate chains of Gal beta-1,4-GlcNAc alpha 2,6-sialyltransferase for enzyme activity. Biochim Biophys Acta, 1202, 325-330 (1993)
168.J. A. Martina, J. L. Daniotti & H. J. Maccioni: GM1 synthase depends on N-glycosylation for enzyme activity and trafficking to the Golgi complex. Neurochem Res, 25, 725-731 (2000)
doi:10.1023/A:1007527523734
169.M. Muhlenhoff, A. Manegold, M. Windfuhr, B. Gotza & R. Gerardy-Schahn: The impact of N-glycosylation on the functions of polysialyltransferases. J Biol Chem, 276, 34066-34073 (2001)
doi:10.1074/jbc.M101022200
170.S. Uemura, T. Kurose, T. Suzuki, S. Yoshida, M. Ito, M. Saito, M. Horiuchi, F. Inagaki, Y. Igarashi & J. Inokuchi: Substitution of the N-glycan function in glycosyltransferases by specific amino acids: ST3Gal-V as a model enzyme. Glycobiology, 16, 258-270 (2006)
doi:10.1093/glycob/cwj060
171.L. E. Gerweck & K. Seetharaman: Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res, 56, 1194-1198 (1996)
172.G. R. Martin & R. K. Jain: Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy. Cancer Res, 54, 5670-5674 (1994)
173.S. Kellokumpu, R. Sormunen & I. Kellokumpu: Abnormal glycosylation and altered Golgi structure in colorectal cancer: dependence on intra-Golgi pH. FEBS Lett, 516, 217-224 (2002)
doi:10.1016/S0014-5793(02)02535-8
174.A. Rivinoja, N. Kokkonen, I. Kellokumpu & S. Kellokumpu: Elevated Golgi pH in breast and colorectal cancer cells correlates with the expression of oncofetal carbohydrate T-antigen. J Cell Physiol, 208, 167-174 (2006)
doi:10.1002/jcp.20653
175.A. Rivinoja, A. Hassinen, N. Kokkonen, A. Kauppila & S. Kellokumpu: Elevated Golgi pH impairs terminal N-glycosylation by inducing mislocalization of Golgi glycosyltransferases. J Cell Physiol, 220, 144-154 (2009)
doi:10.1002/jcp.21744
176.C. Chen, J. Ma, A. Lazic, M. Backovic & K. J. Colley: Formation of insoluble oligomers correlates with ST6Gal I stable localization in the golgi. J Biol Chem, 275, 13819-13826 (2000)
doi:10.1074/jbc.275.18.13819
177.A. El-Battari, M. Prorok, K. Angata, S. Mathieu, M. Zerfaoui, E. Ong, M. Suzuki, D. Lombardo & M. Fukuda: Different glycosyltransferases are differentially processed for secretion, dimerization, and autoglycosylation. Glycobiology, 13, 941-953 (2003) doi:10.1093/glycob/cwg117
178.F. H. Fenteany & K. J. Colley: Multiple signals are required for alpha2,6-sialyltransferase (ST6Gal I) oligomerization and Golgi localization. J Biol Chem, 280, 5423-5429 (2005)
doi:10.1074/jbc.M412396200
179.J. Ma & K. J. Colley: A disulfide-bonded dimer of the Golgi beta-galactoside alpha2,6-sialyltransferase is catalytically inactive yet still retains the ability to bind galactose. J Biol Chem, 271, 7758-7766 (1996)
doi:10.1074/jbc.271.13.7758
180.S. Tsuji, A. K. Datta & J. C. Paulson: Systematic nomenclature for sialyltransferases. Glycobiology, 6, v-vii (1996)
doi:10.1093/glycob/6.7.647-a
181.L. Svennerholm: The Gangliosides. J Lipid Res, 5, 145-155 (1964)
182.N. Matsuura, T. Narita, N. Hiraiwa, M. Hiraiwa, H. Murai, T. Iwase, H. Funahashi, T. Imai, H. Takagi & R. Kannagi: Gene expression of fucosyl- and sialyl-transferases which synthesize sialyl Lewisx, the carbohydrate ligands for E-selectin, in human breast cancer. Int J Oncol, 12, 1157-1164 (1998)
183.J. Muthing, I. Meisen, B. Kniep, J. Haier, N. Senninger, U. Neumann, M. Langer, K. Witthohn, J. Milosevic & J. Peter-Katalinic: Tumor-associated CD75s gangliosides and CD75s-bearing glycoproteins with Neu5Acalpha2-6Galbeta1-4GlcNAc-residues are receptors for the anticancer drug rViscumin. Faseb J, 19, 103-105 (2005)
doi: 10.1096/fj.04-2494fje
184.A. Cazet, S. Groux-Degroote, B. Teylaert, K. M. Kwon, S. Lehoux, C. Slomianny, C. H. Kim, X. Le Bourhis & P. Delannoy: GD3 synthase overexpression enhances proliferation and migration of MDA-MB-231 breast cancer cells. Biol Chem, 390, 601-609 (2009)
doi:10.1515/BC.2009.054
185.B. D. Livingston, J. L. Jacobs, M. C. Glick & F. A. Troy: Extended polysialic acid chains (n greater than 55) in glycoproteins from human neuroblastoma cells. J Biol Chem, 263, 9443-9448 (1988)
186.M. H. Shah, S. D. Telang, P. M. Shah & P. S. Patel: Tissue and serum alpha 2-3- and alpha 2-6-linkage specific sialylation changes in oral carcinogenesis. Glycoconj J, 25, 279-290 (2008)
doi:10.1007/s10719-007-9086-4
187.F. Dall'Olio, M. Chiricolo, A. D'Errico, E. Gruppioni, A. Altimari, M. Fiorentino & W. F. Grigioni: Expression of beta-galactoside alpha2,6 sialyltransferase and of alpha2,6-sialylated glycoconjugates in normal human liver, hepatocarcinoma, and cirrhosis. Glycobiology, 14, 39-49 (2004)
doi:10.1093/glycob/cwh002
188.F. L. Wang, S. X. Cui, L. P. Sun, X. J. Qu, Y. Y. Xie, L. Zhou, Y. L. Mu, W. Tang & Y. S. Wang: High expression of alpha 2, 3-linked sialic acid residues is associated with the metastatic potential of human gastric cancer. Cancer Detect Prev, 32, 437-443 (2009)
doi:10.1016/j.cdp.2009.01.001
189.M. Chovanec, J. Plzak, J. Betka, J. Brabec, R. Kodet & K. Smetana, Jr.: Comparative analysis of alpha2,3/2,6-linked N-acetylneuraminic acid and cytokeratin expression in head and neck squamous cell carcinoma. Oncol Rep, 12, 297-301 (2004)
Footnotes: The nomenclature of sialyltransferases is based on Tsuji et al. (180) and the nomenclature of glycolipids is based on Svennerholm (181)
Key Words: Cancer, sialyltransferase, Golgi, sialylation Review
Send correspondence to: Anne Harduin-Lepers, Unite de Glycobiologie Structurale et Fonctionnelle, Universite Lille Nord de France, Lille1, CNRS UMR 8576, 59655 Villeneuve d'Ascq, France, Tel: 33320336246, Fax: 33320436555, E-mail:anne.harduin@univ-lille1.fr