O-GlcNAcylation mediates metastasis of cholangiocarcinoma through FOXO3 and MAN1A1
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
The leading cause of death in cancer patients is metastasis, for which an effective treatment is still necessary. During metastasis, cancer cells aberrantly express several glycans that are correlated with poor patient outcome. This study was aimed toward exploring the effects of O-GlcNAcylation on membranous N-glycans that are associated with the progression of cholangiocarcinoma (CCA). Global O-GlcNAcylation in CCA cells was depleted using specific siRNA against O-GlcNAc transferase (OGT), which transfers GlcNAc to the acceptor proteins. Using an HPLC-Chip/Time-of-Flight (Chip/TOF) MS system, the N-glycans associated with O-GlcNAcylation were identified by comparing the membranous N-glycans of siOGT-treated cells with those of scramble siRNA-treated cells. In parallel, the membranous N-glycans of the parental cells (KKU-213 and KKU-214) were compared with those of the highly metastatic cells (KKU-213L5 and KKU-214L5). Together, these data revealed that high mannose (Hex9HexNAc2) and biantennary complex (Hex5HexNAc4Fuc1NeuAc1) N-linked glycans correlated positively with metastasis. We subsequently demonstrate that suppression of O-GlcNAcylation decreased the expression of these two N-glycans, suggesting that O-GlcNAcylation mediates their levels in CCA. In addition, the ability of highly metastatic cells to migrate and invade was reduced by the presence of Pisum Sativum Agglutinin (PSA), a mannose-specific lectin, further indicating the association of high mannose type N-glycans with CCA metastasis. The molecular mechanism of O-GlcNAc-mediated progression of CCA was shown to proceed via a series of signaling events, involving the activation of Akt/Erk (i), an increase in FOXO3 phosphorylation (ii), which results in the reduction of MAN1A1 expression (iii) and thus the accumulation of Hex9HexNAc2 N-glycans (iv). This study demonstrates for the first time the association between O-GlcNAcylation, high mannose type N-glycans, and the progression of CCA metastasis, suggesting a novel therapeutic target for treatment of metastatic CCA.
Date Issued
2018-06-18
Date Acceptance
2018-05-25
Citation
Oncogene, 2018, 37, pp.5648-5665
ISSN
0950-9232
Publisher
Nature Publishing Group
Start Page
5648
End Page
5665
Journal / Book Title
Oncogene
Volume
37
Copyright Statement
© The Author(s) 2018. This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as
long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons license, and indicate if
changes were made. The images or other third party material in this
article are included in the article
’
s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not
included in the article
’
s Creative Commons license and your intended
use is not permitted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from the copyright
holder. To view a copy of this license, visit
http://creativecommons.
org/licenses/by/4.0/
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as
long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons license, and indicate if
changes were made. The images or other third party material in this
article are included in the article
’
s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not
included in the article
’
s Creative Commons license and your intended
use is not permitted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from the copyright
holder. To view a copy of this license, visit
http://creativecommons.
org/licenses/by/4.0/
Sponsor
Breast Cancer Campaign
Cancer Research UK
Breast Cancer Now
Breast Cancer Now
Medical Research Council (MRC)
Grant Number
2007NovPhD16
C37/A12011
2012NovemberPhD016
2012MayPR070
MR/N012097/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
ABERRANT GLYCOSYLATION
N-ACETYLGLUCOSAMINE
CANCER
CELLS
TRANSCRIPTION
EXPRESSION
OLIGOSACCHARIDES
AGGRESSIVENESS
RELEVANCE
INVASION
Acylation
Bile Duct Neoplasms
Cell Line, Tumor
Cholangiocarcinoma
Forkhead Box Protein O3
Gene Expression Regulation, Neoplastic
Humans
Membrane Proteins
Neoplasm Invasiveness
Nuclear Proteins
Polysaccharides
Cell Line, Tumor
Humans
Cholangiocarcinoma
Bile Duct Neoplasms
Neoplasm Invasiveness
Polysaccharides
Membrane Proteins
Nuclear Proteins
Gene Expression Regulation, Neoplastic
Acylation
Forkhead Box Protein O3
Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
1103 Clinical Sciences
Publication Status
Published
Date Publish Online
2018-06-18