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Gene Section
Review
ST6GALNAC1 (ST6 (alpha-N-acetyl-neuraminyl2,3-beta-galactosyl-1,3)-N-acetylgalacto-saminide
alpha-2,6-sialyltransferase 1)
Philippe Delannoy, Anne Harduin-Lepers, Marie-Ange Krzewinski-Recchi
Structural and Functional Glycobiology Unit, UMR CNRS 8576, University of Lille, Villeneuve d'Ascq,
France (PD, AHL, MAKR)
Published in Atlas Database: March 2008
Online updated version: http://AtlasGeneticsOncology.org/Genes/ST6GALNAC1ID44087ch17q25.html
DOI: 10.4267/2042/44389
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
transcript, but it is not expressed in spleen, brain, or
pancreas. ST6GalNAc I transcripts were also detected
in intestinal metaplasia and duodenal mucosa. In situ
hybridization demonstrated that the localization of
transcripts correlated well with that of STn antigen in
gastric cancer cells and Goblet cells in intestinal
metaplastic glands (Ikehara et al., 1999).
RT-PCR analysis shows that ST6GalNAc I gene is
expressed only in a limited number of cultured cancer
cells, including HT29 and Dami cells (Figure 2).
ST6GalNAc I ESTs have been obtained in bone
marrow, cervix, esophagus, intestine, skeletal muscle,
prostate, spleen, stomach, tongue and trachea, and in
several cancer tissues, including cervical, esophageal,
prostate, stomach and uterine cancers.
Two cDNA of about 2.5 and 2.3 kp have been isolated.
The longer cDNA encodes a 600 amino acids protein
(DDBJ/EMBL/GenBank # Y11339).
Identity
Other names: HSY11339; SIAT7A; ST6GalNAcI
HGNC (Hugo): ST6GALNAC1
Location: 17q25.1
Local order: 72, 132,442-72, 151,489.
DNA/RNA
Description
ST6GalNAc I gene is located on chromosome 17, at
location 72,132,442-72,151,489, spans 19.05 kb and
contains 9 exons. The start of this gene is located in
Contig AC005837.1.1.163218.
Transcription
Northern blot analysis has shown that ST6GalNAc I
gene is expressed in pyloric mucosa as a single 2.5 kb
Figure 1. Genomic organization of human ST6GalNAc I gene. The gene is located on chromosome 17q25.1, spans 19.05 kb and
contains 9 exons labeled El-E9.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1)
70
ST6GALNAC1 (ST6 (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide
alpha-2,6-sialyltransferase 1)
Delannoy P, et al.
Figure 2. RT-PCR analysis of the expression of hST6GalNAc I in various human cancer lines
The shorter cDNA shows a nucleotide sequence
identical to that of the longer form except for the lack
of a 234 bp segment at nucleotide positions 652-885
(relative to the ATG of the long-form (# Y11339)). The
short-form cDNA would encode a protein that lacks a
78 amino acid fragment at positions 218-295 in the
catalytic region (Ikehara et al., 1999).
Expression
The stable transfection of MDA-MB-231 or T47D
breast cancer cells with an expression vector encoding
ST6GalNAc I induces the expression of STn antigen at
the cell surface, which is carried by several high
molecular weight membrane bound O-glycoproteins,
including MUC1 (Julien et al., 2001; Julien et al.,
2005). Sialyl-Tn expression is associated with
morphological changes, decreased growth and
adhesion, and increased cell migration of sialyl-Tn
positive clones. STn positive MDA-MB-231 breast
cancer cells exhibit an increased tumor growth in SCID
mice (Julien et al., 2006). The MKN45 gastric cell line
stably transfected with the full length ST6GalNAc-I
also showed high expression of Sialyl-Tn antigen
(Marcos et al., 2004). In breast carcinomas, a complete
correlation between the expression of ST6GalNAc-I
and the expression of sialyl-Tn has been shown (Sewell
et al., 2006).
Pseudogene
No ST6GalNAc I pseudogene has been identified in the
human genome.
Protein
Note
CMP-NeuAc:
N-acetyl-galactosaminide-alpha1-OSer/Thr alpha2,6-sialyltransferase 1; synonyms:
SIAT7A, HSY11339, hSTYI, ST6GalNAc I
Description
The human ST6GalNAc I (EC 2.4.99.3, CAZy Family
GT29, CMP-NeuAc R-GalNAc-alpha1-O-Ser/Thr
alpha2,6-sialyltransferase, with R = H, Gal-beta1-3, or
NeuAc-alpha2-3Gal-beta1-3) is a 600 AA type II
membrane-bound sialyltransferase. It shares the same
typical
organization
with
other
Golgi
glycosyltransferases with a short N-terminal domain in
the cytoplasm of the cell, a trans-membrane domain
(TMD), an unusually long stem region and a catalytic
domain oriented in the lumen of Golgi cisternae. The
enzyme possess the 4 signature motifs (sialylmotifs L,
S, VS and motif III) of mammalian sialyltransferases
(Harduin-Lepers et al., 2005; Jeanneau et al., 2004) and
the ST6GalNAc A family-motifs (Patel Balaji, 2006).
No 3D structure is available. The enzyme transfers a
sialic acid (N-acetylneuraminic acid) from CMPNeuAc in the 6-position of a GalNAc residue linked to
a serine or a threonine residue of a mucin-type
glycopeptide or glycoprotein. The human ST6GalNAc
I accepts the following structures as acceptor substrate:
GalNAc-alpha-O-Ser/Thr, Gal-beta1-3GalNAc-alphaO-Ser/Thr and Neu5Ac-alpha2-3Gal-beta1-3GalNAcalpha-O-Ser/Thr (Ikehara et al., 1999).
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1)
Localisation
ST6GalNAc I is a Golgi-resident glycosyltrans-ferase.
Function
The Human ST6GalNAc I is a sialyltransferase
involved in the biosynthesis of the carbohydrate moiety
of mucin-type O-linked glycan chains, transferring a
sialic acid residue in 6-position of the first GalNAc
residue linked to the peptide aglycone. ST6GalNAc I is
particularly involved in the biosynthesis of the sialylTn antigen (STn, NeuAc-alpha2-6GalNAc-alpha1-OSer/Thr) and also participates to the biosynthesis of
sialyl-6-T
(Gal-beta1-3[NeuAc-alpha2-6]GalNAcalpha1-O-Ser/Thr) and disialyl-T antigens (NeuAcalpha2-3Gal-beta1-3[NeuAc-alpha2-6]GalNAc-alpha1O-Ser/Thr) (Figure 4). ST6GalNAc I compete with Oglycans elongating glycosyltransferases and prevent
cancer cells to exhibit longer O-glycans. While fetal
and normal adult tissues weakly express STn, the
antigen is over-expressed in a wide range of epithelial
cancers and is considered as a good maker of tumor.
71
ST6GALNAC1 (ST6 (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide
alpha-2,6-sialyltransferase 1)
Delannoy P, et al.
Figure 3. Logos representing the ST6GalNAc A family-motifs. (Patel Balaji, 2006).
Figure 4. Sialylation reactions in the initial steps of the O-glycans biosynthesis. The name of the compound is indicated underneath the
glycan structure. The sialic acid residue transferred is indicated in bold characters. The enzymes are indicated in italic and the question
mark indicates that the enzyme is not characterized (from Harduin-Lepers et al., 2001).
The prognostic value of STn expression has been
widely studied, especially in gastric, colorectal, ovarian
and breast cancers, and is correlated to a decreased
survival of the patients.
Mutations
Note
Mutation analysis showed a heterozygous transition
(g.136T→C) leading to p.V80A with a frequency of
9.3% in 32 unrelated control individuals. No other
exonic sequence variations were found. In addition, one
intronic (g.IVS8-24G→A) and one 3' UTR SNP
(g.1653A→G) was found (Meuleman et al., 2001).
Homology
ST6GalNAc I is a sialyltransferase (GT-family #29 in
the CAZy classification) belonging to the ST6GalNAc
family. The amino acid sequence in the catalytic region
of human ST6GalNAc I (250 amino acid residues from
the C-terminal end) shows sequence identity to mouse
ST6GalNAc I (85%), chick ST6GalNAc I (67.2%),
62% homology to human ST6GalNAc II, 36.4% to
human ST6GalNAc III, 35.5% to human ST6GalNAc
IV, 37.6% to human ST6GalNAc V, and 36.6% to
human ST6GalNAc VI.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1)
Implicated in
Note
ST6GALNAC1 encodes a specific CMP-Neu5Ac:
GalNAc a2,6-sialyltransferase termed ST6GalNAc I
responsible for the biosynthesis of sialyl-Tn (STn)
72
ST6GALNAC1 (ST6 (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide
alpha-2,6-sialyltransferase 1)
antigen (Ikehara et al., 1999). STn is over-expressed in
a wide range of epithelial cancers and is considered as a
good tumoral maker. However, its pattern of expression
varies according to the cell morphology and
differentiation, which depend on the cancer type. STn
seems to be related to invasive behavior and metastatic
potential of the cancer cells, while the involved
mechanisms remain unclear. The prognostic value of
STn expression has been widely studied, especially in
pancreas, gastric, colorectal, and ovarian cancers and
breast cancers. For all the cases, the antigen detection is
correlated to a decreased survival of the patients.
The activity of core 1 beta3-Gal-transferase seems to be
an important determinant of the STn phenotype of
colon cancer cells (Brockhausen et al., 2001). Cell
surface-expressed STn in colon cancer is
predominantly carried on high molecular weight splice
variants of CD44 (Singh et al., 2001). Pre-operative
serum level of STn predicts recurrence after curative
surgery in node-negative colorectal cancer patients
(Takahashi et al., 1993).
Prognosis
Poor, decreased survival of the patients
Breast Cancer
Pancreas Cancer
Note
ST6GalNAc I is responsible for the synthesis of the
tumor-associated STn O-glycan in human breast cancer
(Sewell et al., 2006). However, established breast
cancer cell-lines express neither ST6GalNAc I nor STn
(Julien et al., 2001). Stable transfection of MDA-MB231 cells with ST6GalNAc I cDNA induces STn
antigen
expression
together
with
important
modifications of the O-glycosylation pattern of MUC1
in MDA-MB-231 and T-47D cells (Julien et al., 2001;
Julien et al., 2005). ST6GalNAc I expression induces a
decrease of adhesion and an increase of migration of
MDA-MB-231. Moreover, ST6GalNAc I positive
clones exhibit an increased tumor growth in SCID
mice, suggesting that ST6GalNAc I expression is
sufficient to enhance the tumorigenicity of MDA-MB231 breast cancer cells (Julien et al., 2006).
Prognosis
Poor, decreased survival of the patients.
Note
Enhanced expression of Tn and STn antigens is usually
observed in pancreas cancer. STn is expressed in intraepithelial neoplasms of the pancreas concomitantly
with aberrant expression of MUC5AC and MUC6
gastric mucins (Kim et al., 2002). High serum
concentrations of STn are also observed in pancreas
carcinomas (Nanashima et al., 1999). STn appears to be
a more specific tumor marker in pancreas cancer than
Tn antigen (Ching et al., 1994). STn has been also
reported in benign pancreatic intraepithelial neoplasia
stage III (PanIN3), the last histologic grade relevant to
benign tumor before that the tumor become invasive
(Hruban et al., 2000; Kim et al., 2002).
Prognosis
Poor, decreased survival of the patients.
Gastric Cancer
Note
STn antigen is over-expressed in gastric carcinomas
and associated with MUC1 mucin VNTR polymerphism (Santos-Silva et al., 2005). STn is also a useful
predictor of poor prognosis in patients with advanced
stomach cancer (Terashima et al., 1998). In particular,
pre-operative serum levels of STn predict liver
metastasis and poor prognosis in patients with gastric
cancer (Nakagoe et al., 2001). STn is able to modulate
the malignant phenotype inducing a more aggressive
cell behavior, a decreased cell-cell aggregation and an
increased ECM adhesion, migration and invasion
(Pinho et al., 2007). However, the expression of
ST6GalNAc I is low in gastric carcinoma cell lines, in
accordance with the low/absent expression of the STn
(Ogata et al., 2001).
Prognosis
Poor, decreased survival of the patients.
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STn is strongly expressed in a large number of
colorectal carcinomas. However, not correlation was
found between STn antigen tissue expression and
ST6GalNAc I activity levels in colorectal cancer, in
spite of the overexpression of the antigen in tumorous
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This article should be referenced as such:
Delannoy P, Harduin-Lepers A, Krzewinski-Recchi MA.
ST6GALNAC1 (ST6 (alpha-N-acetyl-neuraminyl-2,3-betagalactosyl-1,3)-N-acetylgalactosaminide
alpha-2,6sialyltransferase 1). Atlas Genet Cytogenet Oncol Haematol.
2009; 13(1):70-74.
Marcos NT, Pinho S, Grandela C, Cruz A, Samyn-Petit B,
Harduin-Lepers A, Almeida R, Silva F, Morais V, Costa J,
Kihlberg J, Clausen H, Reis CA. Role of the human
ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancerassociated sialyl-Tn antigen. Cancer Res. 2004 Oct
1;64(19):7050-7
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1)
Delannoy P, et al.
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