De novo expression of human polypeptide N-acetylgalactosaminyltransferase 6 (GalNAc-T6) in colon adenocarcinoma inhibits the differentiation of colonic epithelium
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De novo expression of human polypeptide N-acetylgalactosaminyltransferase 6 (GalNAc-T6) in colon adenocarcinoma inhibits the differentiation of colonic epithelium. / Lavrsen, Kirstine; Dabelsteen, Sally; Vakhrushev, Sergey Y; Levann, Asha M R; Haue, Amalie Dahl; Dylander, August; Mandel, Ulla; Hansen, Lars; Frödin, Morten; Bennett, Eric P; Wandall, Hans H.
In: The Journal of Biological Chemistry, Vol. 293, 2018, p. 1298-1314.Research output: Contribution to journal › Journal article › peer-review
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T1 - De novo expression of human polypeptide N-acetylgalactosaminyltransferase 6 (GalNAc-T6) in colon adenocarcinoma inhibits the differentiation of colonic epithelium
AU - Lavrsen, Kirstine
AU - Dabelsteen, Sally
AU - Vakhrushev, Sergey Y
AU - Levann, Asha M R
AU - Haue, Amalie Dahl
AU - Dylander, August
AU - Mandel, Ulla
AU - Hansen, Lars
AU - Frödin, Morten
AU - Bennett, Eric P
AU - Wandall, Hans H
N1 - Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
PY - 2018
Y1 - 2018
N2 - Aberrant expression of O-glycans is a hallmark of epithelial cancers. Mucin type O-glycosylation is initiated by a large family of UDP-GalNAc:polypeptide N-acetyl-galactosaminyltransferases (GalNAc-Ts), that target different proteins and are differentially expressed in cells and organs. Here we investigated the expression patterns of all of the GalNAc-Ts in colon cancer by analysing transcriptomic data. We found that GalNAc-T6 was highly upregulated in colon adenocarcinomas but absent in normal-appearing adjacent colon tissue. The results were verified by immunohistochemistry, suggesting that GalNAc-T6 plays a role in colon carcinogenesis. To investigate the function of GalNAc-T6 in colon cancer, we used precise gene targeting to produce isogenic colon cancer cell lines with a knockout/-rescue system for GalNAc-T6. GalNAc-T6 expression was associated with a cancer-like, dysplastic growth pattern, whereas GalNAc-T6 knockout cells showed a more normal differentiation pattern, reduced proliferation, normalized cell-cell adhesion, and formation of crypts in tissue cultures. O-glycoproteomic analysis of the engineered cell lines identified a small set of GalNAc-T6-specific targets, suggesting that this isoform has unique cellular functions. In support of this notion, the genetically and functionally closely related GalNAc-T3 homologue did not shown compensatory functionality for effects observed for GalNAc-T6. Taken together, these data strongly suggest that aberrant GalNAc-T6 expression and site-specific glycosylation is involved in oncogenic transformation.
AB - Aberrant expression of O-glycans is a hallmark of epithelial cancers. Mucin type O-glycosylation is initiated by a large family of UDP-GalNAc:polypeptide N-acetyl-galactosaminyltransferases (GalNAc-Ts), that target different proteins and are differentially expressed in cells and organs. Here we investigated the expression patterns of all of the GalNAc-Ts in colon cancer by analysing transcriptomic data. We found that GalNAc-T6 was highly upregulated in colon adenocarcinomas but absent in normal-appearing adjacent colon tissue. The results were verified by immunohistochemistry, suggesting that GalNAc-T6 plays a role in colon carcinogenesis. To investigate the function of GalNAc-T6 in colon cancer, we used precise gene targeting to produce isogenic colon cancer cell lines with a knockout/-rescue system for GalNAc-T6. GalNAc-T6 expression was associated with a cancer-like, dysplastic growth pattern, whereas GalNAc-T6 knockout cells showed a more normal differentiation pattern, reduced proliferation, normalized cell-cell adhesion, and formation of crypts in tissue cultures. O-glycoproteomic analysis of the engineered cell lines identified a small set of GalNAc-T6-specific targets, suggesting that this isoform has unique cellular functions. In support of this notion, the genetically and functionally closely related GalNAc-T3 homologue did not shown compensatory functionality for effects observed for GalNAc-T6. Taken together, these data strongly suggest that aberrant GalNAc-T6 expression and site-specific glycosylation is involved in oncogenic transformation.
U2 - 10.1074/jbc.M117.812826
DO - 10.1074/jbc.M117.812826
M3 - Journal article
C2 - 29187600
VL - 293
SP - 1298
EP - 1314
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
ER -
ID: 186445921