DNA hypermethylation contributes to incomplete synthesis of carbohydrate determinants in gastrointestinal cancer.
OBJECTIVE
It has long been known that malignant transformation is associated with abnormal expression of carbohydrate determinants. The aim of this study was to clarify the cause of cancer-associated abnormal glycosylation in gastrointestinal (GI) cancers.


METHODS
We compared the expression levels of "glyco-genes," including glycosyltransferases and glycosidases, in normal GI mucosa and in gastric and colorectal cancer cells. To examine the possibility that DNA hypermethylation contributed to the down-regulation of these genes, we treated GI cancer cells with 5-aza-2'-deoxycytidine (5-aza-dC), an inhibitor of DNA methyltransferase.


RESULTS
The silencing of some of these glyco-genes, but not up-regulation of certain molecules, was observed. The Sd(a) carbohydrate was abundantly expressed in the normal GI mucosa, but its expression was significantly decreased in cancer tissues. When human colon and gastric cancer cells were treated with 5-aza-dC, cell surface expression of Sd(a) and the transcription of B4GALNT2, which catalyzes the synthesis of the Sd(a), were induced. The promoter region of the human B4GALNT2 gene was heavily hypermethylated in many of the GI cancer cell lines examined as well as in gastric cancer tissues (39 out of 78 cases). In addition, aberrant methylation of the B4GALNT2 gene was strongly correlated with Epstein-Barr virus-associated gastric carcinomas and occurred coincidentally with hypermethylation of the ST3GAL6 gene.


CONCLUSIONS
Epigenetic changes in a group of glycosyltransferases including B4GALNT2 and ST3GAL6 represent a malignant phenotype of gastric cancer caused by silencing of the activity of these enzymes, which action may eventually induce aberrant glycosylation and expression of cancer-associated carbohydrate antigens.
Kawamura
Yuki I
YI
Department of Gastroenterology, Research Institute, International Medical Center of Japan, Tokyo, Japan.
Toyota
Minoru
M
Kawashima
Rei
R
Hagiwara
Teruki
T
Suzuki
Hiromu
H
Imai
Kohzoh
K
Shinomura
Yasuhisa
Y
Tokino
Takashi
T
Kannagi
Reiji
R
Dohi
Taeko
T
D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics; D002241:Carbohydrates; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020031:Epstein-Barr Virus Infections / Q000235:genetics; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics* / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D006801:Humans; D008297:Male; D008875:Middle Aged; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012799:Sialyltransferases / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
D000951:Antigens, Neoplasm; D002241:Carbohydrates; D016159:Tumor Suppressor Protein p53; D005700:Galactosyltransferases; D017350:N-Acetylgalactosaminyltransferases; C071413:beta-1,4-N-acetyl-galactosaminyl transferase 2; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase; C000722087:ST3GAL1 protein, human