Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways
Alteration of mucin-type O-glycosylation is implicated in tumor progression and metastasis of cholangiocarcinoma (CCA). Core 1 β1-3 Galactosyltransferase (C1GALT1) is a primary enzyme that regulates the elongation of core 1-derived mucin-type O-glycans. Dysregulation of C1GALT1 has been documented i...
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MDPI AG
2022-01-01
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| Series: | Life |
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| Online Access: | https://www.mdpi.com/2075-1729/12/2/174 |
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| author | Juthamas Khiaowichit Chutima Talabnin Chavaboon Dechsukhum Atit Silsirivanit Krajang Talabnin |
| author_facet | Juthamas Khiaowichit Chutima Talabnin Chavaboon Dechsukhum Atit Silsirivanit Krajang Talabnin |
| author_sort | Juthamas Khiaowichit |
| collection | DOAJ |
| description | Alteration of mucin-type O-glycosylation is implicated in tumor progression and metastasis of cholangiocarcinoma (CCA). Core 1 β1-3 Galactosyltransferase (C1GALT1) is a primary enzyme that regulates the elongation of core 1-derived mucin-type O-glycans. Dysregulation of C1GALT1 has been documented in multiple cancers and is associated with aberrant core 1 O-glycosylation and cancer aggressiveness; however, the expression of C1GALT1 and its role in CCA progression remains unknown. Our study demonstrated that C1GALT1 was downregulated in CCA tissues at both the mRNA and protein levels. The biological function of C1GALT1 using siRNA demonstrated that suppression of C1GALT1 in the CCA cell lines (KKU-055 and KKU-100) increased CCA progression, evidenced by: (i) Induction of CCA cell proliferation and 5-fluorouracil resistance in a dose-dependent manner; (ii) up-regulation of growth-related genes, ABC transporter genes, and anti-apoptotic proteins; and (iii) an increase in the activation/phosphorylation of AKT and ERK in silencing C1GALT1 cells. We demonstrated that silencing C1GALT1 in CCA cell lines was associated with immature core 1 O-glycosylation, demonstrated by high expression of VVL-binding glycans and down-regulation of other main O-linked glycosyltransferases β1,3-N-acetylglucosaminyltransferase 6 (<i>B3GNT6</i>) and ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 (<i>ST6GALNAC1</i>) in C1GALT1 knockdown. Our findings demonstrate that down-regulation of C1GALT1 in CCA increases the expression of immature core 1 O-glycan, enhancing CCA progression, including growth and 5-fluorouracil resistance via the activation of the AKT/ERK signaling pathway. |
| first_indexed | 2024-03-09T21:35:14Z |
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| issn | 2075-1729 |
| language | English |
| last_indexed | 2024-03-09T21:35:14Z |
| publishDate | 2022-01-01 |
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| series | Life |
| spelling | doaj.art-4bda3892068e4307a0a0bdedc997e9462023-11-23T20:45:16ZengMDPI AGLife2075-17292022-01-0112217410.3390/life12020174Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling PathwaysJuthamas Khiaowichit0Chutima Talabnin1Chavaboon Dechsukhum2Atit Silsirivanit3Krajang Talabnin4School of Translational Medicine, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima 30000, ThailandSchool of Chemistry, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, ThailandSchool of Pathology, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima 30000, ThailandDepartment of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, ThailandSchool of Pathology, Institute of Medicine, Suranaree University of Technology, Nakhon Ratchasima 30000, ThailandAlteration of mucin-type O-glycosylation is implicated in tumor progression and metastasis of cholangiocarcinoma (CCA). Core 1 β1-3 Galactosyltransferase (C1GALT1) is a primary enzyme that regulates the elongation of core 1-derived mucin-type O-glycans. Dysregulation of C1GALT1 has been documented in multiple cancers and is associated with aberrant core 1 O-glycosylation and cancer aggressiveness; however, the expression of C1GALT1 and its role in CCA progression remains unknown. Our study demonstrated that C1GALT1 was downregulated in CCA tissues at both the mRNA and protein levels. The biological function of C1GALT1 using siRNA demonstrated that suppression of C1GALT1 in the CCA cell lines (KKU-055 and KKU-100) increased CCA progression, evidenced by: (i) Induction of CCA cell proliferation and 5-fluorouracil resistance in a dose-dependent manner; (ii) up-regulation of growth-related genes, ABC transporter genes, and anti-apoptotic proteins; and (iii) an increase in the activation/phosphorylation of AKT and ERK in silencing C1GALT1 cells. We demonstrated that silencing C1GALT1 in CCA cell lines was associated with immature core 1 O-glycosylation, demonstrated by high expression of VVL-binding glycans and down-regulation of other main O-linked glycosyltransferases β1,3-N-acetylglucosaminyltransferase 6 (<i>B3GNT6</i>) and ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 (<i>ST6GALNAC1</i>) in C1GALT1 knockdown. Our findings demonstrate that down-regulation of C1GALT1 in CCA increases the expression of immature core 1 O-glycan, enhancing CCA progression, including growth and 5-fluorouracil resistance via the activation of the AKT/ERK signaling pathway.https://www.mdpi.com/2075-1729/12/2/174cholangiocarcinomacore 1 β1-3 galactosyltransferase 1 (C1GALT1)cancer aggressiveness |
| spellingShingle | Juthamas Khiaowichit Chutima Talabnin Chavaboon Dechsukhum Atit Silsirivanit Krajang Talabnin Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways Life cholangiocarcinoma core 1 β1-3 galactosyltransferase 1 (C1GALT1) cancer aggressiveness |
| title | Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways |
| title_full | Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways |
| title_fullStr | Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways |
| title_full_unstemmed | Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways |
| title_short | Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways |
| title_sort | down regulation of c1galt1 enhances the progression of cholangiocarcinoma through activation of akt erk signaling pathways |
| topic | cholangiocarcinoma core 1 β1-3 galactosyltransferase 1 (C1GALT1) cancer aggressiveness |
| url | https://www.mdpi.com/2075-1729/12/2/174 |
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