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O-GlcNAcylation mediates metastasis of cholangiocarcinoma through FOXO3 and MAN1A1

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Title: O-GlcNAcylation mediates metastasis of cholangiocarcinoma through FOXO3 and MAN1A1
Authors: Phoomak, C
Silsirivanit, A
Park, D
Sawanyawisuth, K
Vaeteewoottacharn, K
Wongkham, C
Lam, EW
Pairojkul, C
Lebrilla, CB
Wongkham, S
Item 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.
Issue Date: 18-Jun-2018
Date of Acceptance: 25-May-2018
URI: http://hdl.handle.net/10044/1/60363
DOI: https://dx.doi.org/10.1038/s41388-018-0366-1
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/
Sponsor/Funder: Breast Cancer Campaign
Cancer Research UK
Breast Cancer Now
Breast Cancer Now
Medical Research Council (MRC)
Funder's Grant Number: 2007NovPhD16
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Genetics & Heredity
Bile Duct Neoplasms
Cell Line, Tumor
Forkhead Box Protein O3
Gene Expression Regulation, Neoplastic
Membrane Proteins
Neoplasm Invasiveness
Nuclear Proteins
Cell Line, Tumor
Bile Duct Neoplasms
Neoplasm Invasiveness
Membrane Proteins
Nuclear Proteins
Gene Expression Regulation, Neoplastic
Forkhead Box Protein O3
Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
1103 Clinical Sciences
Publication Status: Published
Online Publication Date: 2018-06-18
Appears in Collections:Department of Surgery and Cancer