|
1
|
Skurska E, Olczak M. GDP-fucose transporter SLC35C1: a potential regulatory role in cytosolic GDP-fucose and fucosylated glycan synthesis. FEBS Open Bio 2025. [PMID: 40421778 DOI: 10.1002/2211-5463.70057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 04/22/2025] [Accepted: 05/05/2025] [Indexed: 05/28/2025] Open
Abstract
Glycosylation occurs mainly in the Golgi apparatus, whereas the synthesis of nucleotide sugars occurs in the cytoplasm or nucleus. GDP-fucose in mammalian cells could be produced via de novo and salvage pathways in the cytoplasm; the first one is responsible for about 90% of GDP-fucose in the total pool of this nucleotide sugar in the cell. SLC35C1 (C1) is the primary transporter of GDP-fucose to the Golgi apparatus. In the absence of this transporter, it was proposed that nucleotide sugar could still reach the Golgi apparatus via a SLC35C2, the homologue of SLC35C1. However, simultaneous inactivation of the two transporters did not influence GDP-fucose transport across the Golgi apparatus membranes after external fucose supplementation. In this study, we combined the inactivation of SLC35C1 and enzymes of the GDP-fucose biosynthesis pathways (FCSK, GMDS and TSTA3) to study the impact of double inactivation on the production of nucleotide sugar and fucosylated glycans. We found that a lack of SLC35C1 changed the level of enzymes of both de novo and salvage pathways. Upon fucose supplementation, stimulation of the salvage pathway was remarkably high in the absence of the TSTA3 protein, and the concentration of GDP-fucose increased to millimolar values. In this work, we discovered that simultaneous deficiency of the SLC35C1 protein and TSTA3 enzyme increased GDP-fucose production via the salvage pathway to an even higher level. Finally, we found that nucleotide sugar still accessed the Golgi apparatus and had differential effects on N- and O-glycans.
Collapse
Affiliation(s)
- Edyta Skurska
- Faculty of Biotechnology, University of Wroclaw, Poland
| | | |
Collapse
|
|
2
|
Bastian K, Orozco‐Moreno M, Thomas H, Hodgson K, Visser EA, Rossing E, Pijnenborg JFA, Eerden N, Wilson L, Saravannan H, Hanley O, Grimsley G, Frame F, Peng Z, Knight B, McCullagh P, McGrath J, Crundwell M, Harries L, Maitland NJ, Heer R, Wang N, Goddard‐Borger ED, Guerrero RH, Boltje TJ, Drake RR, Scott E, Elliott DJ, Munkley J. FUT8 Is a Critical Driver of Prostate Tumour Growth and Can Be Targeted Using Fucosylation Inhibitors. Cancer Med 2025; 14:e70959. [PMID: 40387385 PMCID: PMC12086987 DOI: 10.1002/cam4.70959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/20/2025] [Accepted: 04/29/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND An unmet clinical need requires the discovery of new treatments for men facing advanced prostate cancer. Aberrant glycosylation is a universal feature of cancer cells and plays a key role in tumour growth, immune evasion and metastasis. Alterations in tumour glycosylation are closely associated with prostate cancer progression, making glycans promising therapeutic targets. Fucosyltransferase 8 (FUT8) drives core fucosylation by adding α1,6-fucose to the innermost GlcNAc residue on N-glycans. While FUT8 is recognised as a crucial factor in cancer progression, its role in prostate cancer remains poorly understood. METHODS & RESULTS Here, we demonstrate using multiple independent clinical cohorts that FUT8 is upregulated in high grade and metastatic prostate tumours, and in the blood of prostate cancer patients with aggressive disease. Using novel tools, including PhosL lectin immunofluorescence and N-glycan MALDI mass spectrometry imaging (MALDI-MSI), we find FUT8 underpins the biosynthesis of malignant core fucosylated N-glycans in prostate cancer cells and using both in vitro and in vivo models, we find FUT8 promotes prostate tumour growth, cell motility and invasion. Mechanistically we show FUT8 regulates the expression of genes and signalling pathways linked to prostate cancer progression. Furthermore, we find that fucosylation inhibitors can inhibit the activity of FUT8 in prostate cancer to suppress the growth of prostate tumours. CONCLUSIONS Our study cements FUT8-mediated core fucosylation as an important driver of prostate cancer progression and suggests targeting FUT8 activity for prostate cancer therapy as an exciting area to explore.
Collapse
Affiliation(s)
- Kayla Bastian
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Margarita Orozco‐Moreno
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Huw Thomas
- Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Paul O'gorman BuildingNewcastle UniversityNewcastle upon TyneUK
| | - Kirsty Hodgson
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Eline A. Visser
- Synthetic Organic Chemistry, Institute for Molecules and MaterialsRadboud UniversityNijmegenthe Netherlands
| | - Emiel Rossing
- Synthetic Organic Chemistry, Institute for Molecules and MaterialsRadboud UniversityNijmegenthe Netherlands
| | | | | | - Laura Wilson
- Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Paul O'gorman BuildingNewcastle UniversityNewcastle upon TyneUK
| | - Hasvini Saravannan
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Oliver Hanley
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Grace Grimsley
- Department of Cell and Molecular PharmacologyMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Fiona Frame
- Cancer Research Unit, Department of BiologyUniversity of YorkNorth YorkshireUK
| | - Ziqian Peng
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Bridget Knight
- NIHR Exeter Clinical Research FacilityRoyal Devon and Exeter NHS Foundation TrustExeterUK
| | - Paul McCullagh
- Department of PathologyRoyal Devon and Exeter NHS Foundation TrustExeterUK
| | - John McGrath
- Exeter Surgical Health Services Research UnitRoyal Devon and Exeter NHS Foundation TrustExeterUK
| | - Malcolm Crundwell
- Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and HealthUniversity of ExeterExeterUK
| | - Lorna Harries
- Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and HealthUniversity of ExeterExeterUK
| | - Norman J. Maitland
- Cancer Research Unit, Department of BiologyUniversity of YorkNorth YorkshireUK
| | - Rakesh Heer
- Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Paul O'gorman BuildingNewcastle UniversityNewcastle upon TyneUK
| | - Ning Wang
- The Mellanby Centre for Musculoskeletal Research, Division of Clinical MedicineThe University of SheffieldSheffieldUK
- Leicester Cancer Research Centre, Department of Genetics, Genomics, and Cancer SciencesUniversity of LeicesterLeicesterUK
| | - Ethan D. Goddard‐Borger
- The Walter and Eliza Hall Institute of Medical ResearchParkvilleVictoriaAustralia
- Department of Medical BiologyUniversity of MelbourneParkvilleVictoriaAustralia
| | - Ramon Hurtado Guerrero
- University of ZaragozaZaragozaSpain
- Copenhagen Center for Glycomics, Department of Cellular and Molecular MedicineUniversity of CopenhagenCopenhagenDenmark
| | - Thomas J. Boltje
- Synthetic Organic Chemistry, Institute for Molecules and MaterialsRadboud UniversityNijmegenthe Netherlands
| | - Richard R. Drake
- Department of Cell and Molecular PharmacologyMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Emma Scott
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - David J. Elliott
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| | - Jennifer Munkley
- Newcastle University Centre for CancerNewcastle University Institute of BiosciencesNewcastleUK
| |
Collapse
|
|
3
|
Chen W, Cheng Q, Li N, Gu K, Zhao H, Na H. The role of glycan-lectin interactions in the tumor microenvironment: immunosuppression regulators of colorectal cancer. Am J Cancer Res 2025; 15:1347-1383. [PMID: 40371166 PMCID: PMC12070101 DOI: 10.62347/wbjl4045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 03/17/2025] [Indexed: 05/16/2025] Open
Abstract
Colorectal cancer (CRC) is a common malignant tumour and a serious global health issue. Glycosylation, a type of posttranslational modification, has been extensively studied in relation to cancer growth and metastasis. Aberrant glycosylation alters how the immune system in the microenvironment perceives the tumour and drives immune suppression through glycan-binding receptors. Interestingly, specific glycan signatures can be regarded as a new pattern of immune checkpoints. Lectins are a group of proteins that exhibit high affinity for glycosylation structures. Lectins and their ligands are found on endothelial cells (ECs), immune cells and tumour cells and play important roles in the tumour microenvironment (TME). In CRC, glycan-lectin interactions can accelerate immune evasion promoting the differentiation of tumour-associated M2 macrophages, altering T cell, dendritic cell (DC), natural killer (NK) cell, and regulatory T (Treg) cell activity to modify the functions of antigen-presenting cells functions. Here, we review our current knowledge on how glycan-lectin interactions affect immune-suppressive circuits in the TME and discuss their roles in the development of more effective immunotherapies for CRC.
Collapse
Affiliation(s)
- Wenbin Chen
- Department of General Surgery, The People’s Hospital of China Medical University and The People’s Hospital of Liaoning ProvinceShenyang 110016, Liaoning, China
| | - Quanzhi Cheng
- Department of Laboratory Medicine, The People’s Hospital of China Medical University and The People’s Hospital of Liaoning ProvinceShenyang 110016, Liaoning, China
| | - Na Li
- Department of Laboratory Medicine, The People’s Hospital of China Medical University and The People’s Hospital of Liaoning ProvinceShenyang 110016, Liaoning, China
| | - Kaiming Gu
- Department of Laboratory Medicine, The People’s Hospital of China Medical University and The People’s Hospital of Liaoning ProvinceShenyang 110016, Liaoning, China
| | - Hongmei Zhao
- Department of Infection Management, The People’s Hospital of China Medical University and The People’s Hospital of Liaoning ProvinceShenyang 110016, Liaoning, China
| | - Heya Na
- Department of Laboratory Medicine, The People’s Hospital of China Medical University and The People’s Hospital of Liaoning ProvinceShenyang 110016, Liaoning, China
| |
Collapse
|
|
4
|
Lee TA, Tsai EY, Liu SH, Chou WC, Hsu Hung SD, Chang CY, Chao CH, Yamaguchi H, Lai YJ, Chen HL, Li CW. Regulation of PD-L1 glycosylation and advances in cancer immunotherapy. Cancer Lett 2025; 612:217498. [PMID: 39855377 DOI: 10.1016/j.canlet.2025.217498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 01/18/2025] [Accepted: 01/22/2025] [Indexed: 01/27/2025]
Abstract
Protein glycosylation plays a versatile role in regulating homeostasis, such as cell migration, protein sorting, and the immune response. Drugs aimed at targeting glycosylation have strong implications for immunity enhancement, diagnosis, and cancer regression. Programmed death-ligand 1 (PD-L1), expressed in cancer or antigen-presenting cells, binds to programmed cell death protein 1 (PD-1) and suppresses T cells. Glycosylation of PD-L1 at N35, N192, N200, and N219 stabilizes PD-L1 on the cancer cell surface, which contributes to immune evasion by inhibiting T cell activity. To date, at least six glycosyltransferases and four associate proteins are known to regulate PD-L1 glycosylation. Terminal modifications such as poly-N-acetyl-lactosamine (poly-LacNAC), sulfation, and sialylation are commonly found on PD-L1, acting as an immune recognition ligand and regulating certain immune responses. Studies have identified many mechanisms and potential therapeutic targets within the glycosylation pathways of PD-L1, revealing their involvement in cancer pathology, immune evasion, and resistance to immunotherapy. In this review, we covered the glycoforms, terminal moiety, binding lectin, glycosyltransferase, as well as sugar analogs focusing on glycosylated PD-L1. We present a mechanism that originates from the endoplasmic reticulum (ER)-Golgi apparatus (Golgi) and its subsequent translocation to the cell membrane. This pathway determines the immune suppression function of PD-L1 and therefore regulates the immune response such as T cells, monocytes, and macrophages. This collection of findings underscores the significance of glycosylation in the role of PD-L1 in cancer and highlights multiple potential targets and strategies for improving therapeutic intervention and diagnostic techniques.
Collapse
Affiliation(s)
- Te-An Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
| | - En-Yun Tsai
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan; School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shou-Hou Liu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
| | - Wen-Cheng Chou
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
| | - Shih-Duo Hsu Hung
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
| | - Chen-Yu Chang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
| | - Chi-Hong Chao
- Center For Intelligent Drug Systems and Smart Bio-devices (IDS(2)B), National Yang Ming Chiao Tung University, Hsinchu, 30010, Taiwan; Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, 30010, Taiwan
| | - Hirohito Yamaguchi
- Graduate Institute of Biomedical Sciences, Graduate Institute of Cell Biology, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan
| | - Yun-Ju Lai
- Solomont School of Nursing, Zuckerberg College of Health Sciences, University of Massachusetts Lowell, 113 Wilder Street, Lowell, MA, 01854, USA
| | - Hung-Lin Chen
- Master Program in Clinical Genomics and Proteomics, Taipei Medical University, Taipei, 11031, Taiwan
| | - Chia-Wei Li
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
| |
Collapse
|
|
5
|
Pan Q, Zhang XL. Roles of core fucosylation modification in immune system and diseases. CELL INSIGHT 2025; 4:100211. [PMID: 39624801 PMCID: PMC11609374 DOI: 10.1016/j.cellin.2024.100211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/01/2024] [Accepted: 10/02/2024] [Indexed: 01/04/2025]
Abstract
Core fucosylation, catalyzed by α1,6-fucosyltransferase (FUT8), is an important N-glycosylation modification process that attaches a fucose residue via an α1,6-linkage to the core N-acetylglucosamine of N-glycans in mammals. Research over the past three decades has revealed the critical role of FUT8-mediated core fucosylation modification in various physiological and pathological processes, including cell growth, adhesion, receptor activation, antibody-dependent cellular cytotoxicity (ADCC), tumor metastasis and infections. This review discusses the immune system function involving FUT8 and the mechanisms by which core fucosylation regulates immunity and contributes to disease. A deeper understanding of these mechanisms can provide insights into cellular biology and suggest new therapeutic approaches and targets for related diseases.
Collapse
Affiliation(s)
- Qiu Pan
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Allergy Zhongnan Hospital of Wuhan University, Department of Immunology Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
- State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Medicine, Wuhan, 430071, China
| | - Xiao-Lian Zhang
- Hubei Province Key Laboratory of Allergy and Immunology, Department of Allergy Zhongnan Hospital of Wuhan University, Department of Immunology Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
- State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Medicine, Wuhan, 430071, China
| |
Collapse
|
|
6
|
Zhu Q, Chaubard JL, Geng D, Shen J, Ban L, Cheung ST, Wei F, Liu Y, Sun H, Calderon A, Dong W, Qin W, Li T, Wen L, Wang PG, Sun S, Yi W, Hsieh-Wilson LC. Chemoenzymatic Labeling, Detection and Profiling of Core Fucosylation in Live Cells. J Am Chem Soc 2024; 146:26408-26415. [PMID: 39279393 DOI: 10.1021/jacs.4c09303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/18/2024]
Abstract
Core fucosylation, the attachment of an α-1,6-linked-fucose to the N-glycan core pentasaccharide, is an abundant protein modification that plays critical roles in various biological processes such as cell signaling, B cell development, antibody-dependent cellular cytotoxicity, and oncogenesis. However, the tools currently used to detect core fucosylation suffer from poor specificity, exhibiting cross-reactivity against all types of fucosylation. Herein we report the development of a new chemoenzymatic strategy for the rapid and selective detection of core fucosylated glycans. This approach employs a galactosyltransferase enzyme identified fromCaenorhabditis elegansthat specifically transfers an azido-appended galactose residue onto core fucose via a β-1,4 glycosidic linkage. We demonstrate that the approach exhibits superior specificity toward core fucose on a variety of complex N-glycans. The method enables detection of core fucosylated glycoproteins from complex cell lysates, as well as on live cell surfaces, and it can be integrated into a diagnostic platform to profile protein-specific core fucosylation levels. This chemoenzymatic labeling approach offers a new strategy for the identification of disease biomarkers and will allow researchers to further characterize the fundamental role of this important glycan in normal and disease physiology.
Collapse
Affiliation(s)
- Qiang Zhu
- College of Life Sciences, Zhejiang University, Hangzhou 310012, China
| | - Jean-Luc Chaubard
- Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125, United States
| | - Didi Geng
- College of Life Sciences, Zhejiang University, Hangzhou 310012, China
| | - Jiechen Shen
- College of Life Sciences, Northwest University, Xi'an 710069, China
| | - Lan Ban
- Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125, United States
| | - Sheldon T Cheung
- Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125, United States
| | - Fangyu Wei
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Medica, The Chinese Academy of Sciences, Shanghai 201203, China
| | - Yating Liu
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Medica, The Chinese Academy of Sciences, Shanghai 201203, China
| | - Haofan Sun
- State Key Laboratory of Proteomics, Beijing Institute of Lifeomics, National Center for Protein Sciences Beijing, Beijing 102206, China
| | - Angie Calderon
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology Institution, Shenzhen, Guangdong 518055, China
| | - Wenbo Dong
- College of Life Sciences, Northwest University, Xi'an 710069, China
| | - Weijie Qin
- State Key Laboratory of Proteomics, Beijing Institute of Lifeomics, National Center for Protein Sciences Beijing, Beijing 102206, China
| | - Tiehai Li
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Medica, The Chinese Academy of Sciences, Shanghai 201203, China
| | - Liuqing Wen
- Carbohydrate-Based Drug Research Center, Shanghai Institute of Materia Medica, The Chinese Academy of Sciences, Shanghai 201203, China
| | - Peng George Wang
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology Institution, Shenzhen, Guangdong 518055, China
| | - Shisheng Sun
- College of Life Sciences, Northwest University, Xi'an 710069, China
| | - Wen Yi
- College of Life Sciences, Zhejiang University, Hangzhou 310012, China
| | - Linda C Hsieh-Wilson
- Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125, United States
| |
Collapse
|
|
7
|
Duan Z, Shi R, Gao B, Cai J. N-linked glycosylation of PD-L1/PD-1: an emerging target for cancer diagnosis and treatment. J Transl Med 2024; 22:705. [PMID: 39080767 PMCID: PMC11290144 DOI: 10.1186/s12967-024-05502-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 07/10/2024] [Indexed: 08/02/2024] Open
Abstract
During tumorigenesis and progression, the immune checkpoint programmed death-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1) play critical roles in suppressing T cell-mediated anticancer immune responses, leading to T-cell exhaustion and subsequent tumor evasion. Therefore, anti-PD-L1/PD-1 therapy has been an attractive strategy for treating cancer over the past decade. However, the overall efficacy of this approach remains suboptimal, revealing an urgent need for novel insights. Interestingly, increasing evidence indicates that both PD-L1 on tumor cells and PD-1 on tumor-specific T cells undergo extensive N-linked glycosylation, which is essential for the stability and interaction of these proteins, and this modification promotes tumor evasion. In various preclinical models, targeting the N-linked glycosylation of PD-L1/PD-1 was shown to significantly increase the efficacy of PD-L1/PD-1 blockade therapy. Furthermore, deglycosylation of PD-L1 strengthens the signal intensity in PD-L1 immunohistochemistry (IHC) assays, improving the diagnostic and therapeutic relevance of this protein. In this review, we provide an overview of the regulatory mechanisms underlying the N-linked glycosylation of PD-L1/PD-1 as well as the crucial role of N-linked glycosylation in PD-L1/PD-1-mediated immune evasion. In addition, we highlight the promising implications of targeting the N-linked glycosylation of PD-L1/PD-1 in the clinical diagnosis and treatment of cancer. Our review identifies knowledge gaps and sheds new light on the cancer research field.
Collapse
Affiliation(s)
- Zhiyun Duan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, P.R. China
| | - Runhan Shi
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, P.R. China
- Department of Ophthalmology and Vision Science, Shanghai Eye Ear Nose and Throat Hospital, Fudan University, Shanghai, 200031, P.R. China
| | - Bo Gao
- Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032, P.R. China
| | - Jiabin Cai
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Liver Cancer Institute, Fudan University, Shanghai, 200032, P.R. China.
- Department of Liver Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, 361015, P.R. China.
| |
Collapse
|
|
8
|
Pan Q, Xie Y, Zhang Y, Guo X, Wang J, Liu M, Zhang XL. EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses. Nat Commun 2024; 15:652. [PMID: 38253527 PMCID: PMC10803816 DOI: 10.1038/s41467-024-44960-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Aberrant N-glycosylation has been implicated in viral diseases. Alpha-(1,6)-fucosyltransferase (FUT8) is the sole enzyme responsible for core fucosylation of N-glycans during glycoprotein biosynthesis. Here we find that multiple viral envelope proteins, including Hepatitis C Virus (HCV)-E2, Vesicular stomatitis virus (VSV)-G, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-Spike and human immunodeficiency virus (HIV)-gp120, enhance FUT8 expression and core fucosylation. HCV-E2 manipulates host transcription factor SNAIL to induce FUT8 expression through EGFR-AKT-SNAIL activation. The aberrant increased-FUT8 expression promotes TRIM40-mediated RIG-I K48-ubiquitination and suppresses the antiviral interferon (IFN)-I response through core fucosylated-EGFR-JAK1-STAT3-RIG-I signaling. FUT8 inhibitor 2FF, N-glycosylation site-specific mutation (Q352AT) of EGFR, and tissue-targeted Fut8 silencing significantly increase antiviral IFN-I responses and suppress RNA viral replication, suggesting that core fucosylation mediated by FUT8 is critical for antiviral innate immunity. These findings reveal an immune evasion mechanism in which virus-induced FUT8 suppresses endogenous RIG-I-mediated antiviral defenses by enhancing core fucosylated EGFR-mediated activation.
Collapse
Grants
- This work was supported by grants from the National Natural Science Foundation of China (82230078, 22077097, 91740120, 82272978, 21572173 and 21721005), National Outstanding Youth Foundation of China (81025008), National Key R&D Program of China (2022YFA1303500, 2018YFA0507603), Medical Science Advancement Program (Basical Medical Sciences) of Wuhan University (TFJC 2018002.), Key R&D Program of Hubei Province (2020BCB020), the Hubei Province’s Outstanding Medical Academic Leader Program (523-276003), the Innovative Group Project of Hubei Health Committee (WJ2021C002), the Foundational Research Funds for the Central University of China (2042022dx0003, 2042023kf1011) and Natural Science Foundation Project of Hubei Province (2021CFB484), Natural Science Foundation Project of Hubei Province (2021CFB484 to M.L).
- This work was supported by grants from the Natural Science Foundation of Hubei Province (2021CFB484), National Natural Science Foundation of China 82272978
Collapse
Affiliation(s)
- Qiu Pan
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
| | - Yan Xie
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
| | - Ying Zhang
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
| | - Xinqi Guo
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
| | - Jing Wang
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China
| | - Min Liu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China.
| | - Xiao-Lian Zhang
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, and Department of Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan, 430071, China.
- Department of Allergy, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, 430071, China.
| |
Collapse
|
|
9
|
Shi M, Nan XR, Liu BQ. The Multifaceted Role of FUT8 in Tumorigenesis: From Pathways to Potential Clinical Applications. Int J Mol Sci 2024; 25:1068. [PMID: 38256141 PMCID: PMC10815953 DOI: 10.3390/ijms25021068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/07/2024] [Accepted: 01/13/2024] [Indexed: 01/24/2024] Open
Abstract
FUT8, the sole glycosyltransferase responsible for N-glycan core fucosylation, plays a crucial role in tumorigenesis and development. Aberrant FUT8 expression disrupts the function of critical cellular components and triggers the abnormality of tumor signaling pathways, leading to malignant transformations such as proliferation, invasion, metastasis, and immunosuppression. The association between FUT8 and unfavorable outcomes in various tumors underscores its potential as a valuable diagnostic marker. Given the remarkable variation in biological functions and regulatory mechanisms of FUT8 across different tumor types, gaining a comprehensive understanding of its complexity is imperative. Here, we review how FUT8 plays roles in tumorigenesis and development, and how this outcome could be utilized to develop potential clinical therapies for tumors.
Collapse
Affiliation(s)
| | | | - Bao-Qin Liu
- Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, Shenyang 110122, China; (M.S.); (X.-R.N.)
| |
Collapse
|
|
10
|
Corcoran E, Olayinka A, di Luca M, Gusti Y, Hakimjavadi R, O'Connor B, Redmond EM, Cahill PA. N-Glycans on the extracellular domain of the Notch1 receptor control Jagged-1 induced Notch signalling and myogenic differentiation of S100β resident vascular stem cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.17.567576. [PMID: 38014317 PMCID: PMC10680845 DOI: 10.1101/2023.11.17.567576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Notch signalling, critical for development and postnatal homeostasis of the vascular system, is highly regulated by several mechanisms including glycosylation. While the importance of O-linked glycosylation is widely accepted, the structure and function of N-glycans has yet to be defined. Here, we take advantage of lectin binding assays in combination with pharmacological, molecular, and site-directed mutagenetic approaches to study N-glycosylation of the Notch1 receptor. We find that several key oligosaccharides containing bisecting or core fucosylated structures decorate the receptor, control expression and receptor trafficking, and dictate Jagged-1 activation of Notch target genes and myogenic differentiation of multipotent S100β vascular stem cells. N-glycans at asparagine (N) 1241 and 1587 protect the receptor from accelerated degradation, while the oligosaccharide at N888 directly affects signal transduction. Conversely, N-linked glycans at N959, N1179, N1489 do not impact canonical signalling but inhibit differentiation. Our work highlights a novel functional role for N-glycans in controlling Notch1 signalling and differentiation of vascular stem cells.
Collapse
Affiliation(s)
- Eoin Corcoran
- Vascular Biology and Therapeutics Laboratory, School of Biotechnology Faculty of Science and Health, Dublin City University, Dublin, Ireland
| | - Abidemi Olayinka
- Vascular Biology and Therapeutics Laboratory, School of Biotechnology Faculty of Science and Health, Dublin City University, Dublin, Ireland
| | - Mariana di Luca
- Vascular Biology and Therapeutics Laboratory, School of Biotechnology Faculty of Science and Health, Dublin City University, Dublin, Ireland
| | - Yusof Gusti
- Vascular Biology and Therapeutics Laboratory, School of Biotechnology Faculty of Science and Health, Dublin City University, Dublin, Ireland
| | - Roya Hakimjavadi
- Vascular Biology and Therapeutics Laboratory, School of Biotechnology Faculty of Science and Health, Dublin City University, Dublin, Ireland
| | - Brendan O'Connor
- School of Biotechnology Faculty of Science and Health, Dublin City University, Dublin, Ireland
| | - Eileen M Redmond
- Department of Surgery, University of Rochester, 601 Elmwood Ave, Rochester, NY 14642, United States
| | - Paul A Cahill
- Vascular Biology and Therapeutics Laboratory, School of Biotechnology Faculty of Science and Health, Dublin City University, Dublin, Ireland
| |
Collapse
|
|
11
|
Lin L, Chen X, Lin G, Chen L, Xu Y, Zeng Y. FUT3 facilitates glucose metabolism of lung adenocarcinoma via activation of NF-κB pathway. BMC Pulm Med 2023; 23:436. [PMID: 37946130 PMCID: PMC10636925 DOI: 10.1186/s12890-023-02688-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 09/28/2023] [Indexed: 11/12/2023] Open
Abstract
OBJECTIVE Fucosyltransferases (FUTs) molecules have been identified to be involved in carcinogenesis of malignant tumors. Nevertheless, the biological function of fucosyltransferases-3 (FUT3) in lung adenocarcinoma (LUAD) malignant phenotype remains unclear. Herein, we investigated the association between FUT3 and LUAD pathological process. METHODS Immunochemistry, RT-qPCR and western blot assays were conducted to evaluate the expression of FUT3 in LUAD and corresponding adjacent tissues. The prognostic value of FUT3 was assessed via Kaplan‑Meier plotter database. The biological process and potential mechanism of FUT3 in LUAD were conducted via GSEA. Additionally, immunofluorescence and metabolite activity detection were performed to determine the potential role of FUT3 in LUAD glucose metabolism. The active biomarkers associated with NF-κB signaling pathway were detected via western blot. Subcutaneous tumor model was conducted to analyze the effect of FUT3 on tumorigenesis of LUAD. RESULTS FUT3 was remarkably upregulated in LUAD tissues compared with adjacent tissues from individuals. FUT3 overexpression may predict poor prognosis of LUAD patients. Knockdown of FUT3 significantly inhibited tumor proliferation, migration and glucometabolic alteration in LUAD cells. Moreover, GSEA demonstrated that elevated FUT3 was positively related to NF-κB signaling pathway. Additionally, in vitro and in vivo assays also indicated that downregulation of FUT3 resulted in the suppression of oncogenesis and glucose metabolism via inactivation of NF-κB pathway. CONCLUSION Our findings demonstrated that FUT3 was involved in glucometabolic process and tumorigenesis of LUAD via NF-κB signaling pathway. FUT3 may be an optimal target for diagnosis and treatment of LUAD patients.
Collapse
Affiliation(s)
- Lanlan Lin
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China
- Fujian Provincial Clinical Research Center of Interventional Respirology, Quanzhou, Fujian Province, 362000, China
- Fujian Provincial Key Laboratory of Lung Stem Cells, Quanzhou, Fujian Province, 362000, China
| | - Xiaohui Chen
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China
- Fujian Provincial Clinical Research Center of Interventional Respirology, Quanzhou, Fujian Province, 362000, China
- Fujian Provincial Key Laboratory of Lung Stem Cells, Quanzhou, Fujian Province, 362000, China
| | - Guofu Lin
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China
- Fujian Provincial Clinical Research Center of Interventional Respirology, Quanzhou, Fujian Province, 362000, China
- Fujian Provincial Key Laboratory of Lung Stem Cells, Quanzhou, Fujian Province, 362000, China
| | - Luyang Chen
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China
- Fujian Provincial Clinical Research Center of Interventional Respirology, Quanzhou, Fujian Province, 362000, China
- Fujian Provincial Key Laboratory of Lung Stem Cells, Quanzhou, Fujian Province, 362000, China
| | - Yuan Xu
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China.
- Fujian Provincial Clinical Research Center of Interventional Respirology, Quanzhou, Fujian Province, 362000, China.
- Clinical Research Center, Quanzhou, Fujian Province, 362000, China.
- School of Public Health, Fujian Medical University, Fuzhou, Fujian Province, 350000, China.
| | - Yiming Zeng
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China.
- Fujian Provincial Clinical Research Center of Interventional Respirology, Quanzhou, Fujian Province, 362000, China.
- Fujian Provincial Key Laboratory of Lung Stem Cells, Quanzhou, Fujian Province, 362000, China.
| |
Collapse
|
|
12
|
Günay B, Matthews E, Morgan J, Tryfonidou MA, Saldova R, Pandit A. An insight on the N-glycome of notochordal cell-rich porcine nucleus pulposus during maturation. FASEB Bioadv 2023; 5:321-335. [PMID: 37554546 PMCID: PMC10405234 DOI: 10.1096/fba.2023-00011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/25/2023] [Accepted: 05/17/2023] [Indexed: 08/10/2023] Open
Abstract
Degeneration of the intervertebral disc is an age-related condition. It also accompanies the disappearance of the notochordal cells, which are remnants of the developmental stages of the nucleus pulposus (NP). Molecular changes such as extracellular matrix catabolism, cellular phenotype, and glycosaminoglycan loss in the NP have been extensively studied. However, as one of the most significant co- and posttranslational modifications, glycosylation has been overlooked in cells in degeneration. Here, we aim to characterize the N-glycome of young and mature NP and identify patterns related to aging. Accordingly, we isolated N-glycans from notochordal cell-rich NP from porcine discs, characterized them using a combined approach of exoglycosidase digestions and analysis with hydrophilic interaction ultra-performance liquid chromatography and mass spectrometry. We have assigned over 300 individual N-glycans for each age group. Moreover, we observed a notable abundance of antennary structures, galactosylation, fucosylation, and sialylation in both age groups. In addition, as indicated from our results, increasing outer arm fucosylation and decreasing α(2,3)-linked sialylation with aging suggest that these traits are age-dependent. Lastly, we have focused on an extensive characterization of the N-glycome of the notochordal cell-rich NP in aging without inferred degeneration, describing glycosylation changes specific for aging only. Our findings in combination with those of other studies, suggest that the degeneration of the NP does not involve identical processes as aging.
Collapse
Affiliation(s)
- Büşra Günay
- CÚRAM SFI Research Centre for Medical DevicesUniversity of GalwayGalwayIreland
| | - Elizabeth Matthews
- NIBRT GlycoScience GroupNational Institute for Bioprocessing Research and Training (NIBRT)DublinIreland
| | - Jack Morgan
- NIBRT GlycoScience GroupNational Institute for Bioprocessing Research and Training (NIBRT)DublinIreland
| | - Marianna A. Tryfonidou
- Faculty of Veterinary Medicine, Department of Clinical SciencesUtrecht UniversityUtrechtThe Netherlands
| | - Radka Saldova
- NIBRT GlycoScience GroupNational Institute for Bioprocessing Research and Training (NIBRT)DublinIreland
- School of Medicine, College of Health and Agricultural ScienceUniversity College DublinDublinIreland
| | - Abhay Pandit
- CÚRAM SFI Research Centre for Medical DevicesUniversity of GalwayGalwayIreland
| |
Collapse
|
|
13
|
Zhang NZ, Zhao LF, Zhang Q, Fang H, Song WL, Li WZ, Ge YS, Gao P. Core fucosylation and its roles in gastrointestinal glycoimmunology. World J Gastrointest Oncol 2023; 15:1119-1134. [PMID: 37546555 PMCID: PMC10401475 DOI: 10.4251/wjgo.v15.i7.1119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/28/2023] [Accepted: 05/08/2023] [Indexed: 07/12/2023] Open
Abstract
Glycosylation is a common post-translational modification in eukaryotic cells. It is involved in the production of many biologically active glycoproteins and the regulation of protein structure and function. Core fucosylation plays a vital role in the immune response. Most immune system molecules are core fucosylated glycoproteins such as complements, cluster differentiation antigens, immunoglobulins, cytokines, major histocompatibility complex molecules, adhesion molecules, and immune molecule synthesis-related transcription factors. These core fucosylated glycoproteins play important roles in antigen recognition and clearance, cell adhesion, lymphocyte activation, apoptosis, signal transduction, and endocytosis. Core fucosylation is dominated by fucosyltransferase 8 (Fut8), which catalyzes the addition of α-1,6-fucose to the innermost GlcNAc residue of N-glycans. Fut8 is involved in humoral, cellular, and mucosal immunity. Tumor immunology is associated with aberrant core fucosylation. Here, we summarize the roles and potential modulatory mechanisms of Fut8 in various immune processes of the gastrointestinal system.
Collapse
Affiliation(s)
- Nian-Zhu Zhang
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Li-Fen Zhao
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Qian Zhang
- Department of Cell Therapy, Shanghai Tianze Yuntai Biomedical Co., Ltd., Shanghai 200100, China
| | - Hui Fang
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-0005, Ibaraki, Japan
| | - Wan-Li Song
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Zhe Li
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Song Ge
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Peng Gao
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| |
Collapse
|
|
14
|
DelaCourt A, Mehta A. Beyond glyco-proteomics-Understanding the role of genetics in cancer biomarkers. Adv Cancer Res 2023; 157:57-81. [PMID: 36725113 DOI: 10.1016/bs.acr.2022.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The development of robust cancer biomarkers is the most effective way to improve overall survival, as early detection and treatment leads to significantly better clinical outcomes. Many of the cancer biomarkers that have been identified and are clinically utilized are glycoproteins, oftentimes a specific glycoform. Aberrant glycosylation is a common theme in cancer, with dysregulated glycosylation driving tumor initiation and metastasis, and abnormal glycosylation can be detection both on the tissue surface and in serum. However, most cancer types are heterogeneous in regard to tumor genomics, and this heterogeneity extends to cancer glycomics. This limits the sensitivity of standalone glycan-based biomarkers, which has slowed their implementation clinically. However, if targeted biomarker development can take into account genomic tumor information, the development of complementary biomarkers that target unique cancer subgroups can be accomplished. This idea suggests the need for algorithm-based cancer biomarkers, which can utilize multiple biomarkers along with relevant demographic information. This concept has already been established in the detection of hepatocellular carcinoma with the GALAD score, and an algorithm-based approach would likely be effective in improving biomarker sensitivity for additional cancer types. In order to increase cancer diagnostic biomarker sensitivity, there must be more targeted biomarker development that considers tumor genomic, proteomic, metabolomic, and clinical data while identifying tumor biomarkers.
Collapse
Affiliation(s)
- Andrew DelaCourt
- Department of Cell & Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States
| | - Anand Mehta
- Department of Cell & Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States.
| |
Collapse
|
|
15
|
Effect and Mechanism Analysis of Pig FUT8 Gene on Resistance to Escherichia coli F18 Infection. Int J Mol Sci 2022; 23:ijms232314713. [PMID: 36499043 PMCID: PMC9739813 DOI: 10.3390/ijms232314713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/16/2022] [Accepted: 11/22/2022] [Indexed: 11/27/2022] Open
Abstract
Post-weaning diarrhea caused by enterotoxigenic Escherichia coli F18 (E. coli F18) causes significant economic losses for pig producers. Fucosyltransferase 8 (FUT8) is a glycosyltransferase that catalyzes core fucosylation; however, its role in mediating the resistance to E. coli F18 infection in pigs remains unknown. In this study, we systematically verified the relationship between FUT8 expression and E. coli resistance. The results showed that FUT8 was expressed in all detected tissues of Meishan piglets and that its expression was significantly increased in the duodenum and jejunum of E. coli F18-sensitive individuals when compared to E. coli F18-resistant individuals. FUT8 expression increased after exposure to E. coli F18 (p < 0.05) and decreased significantly after LPS induction for 6 h (p < 0.01). Then, the IPEC-J2 stable cell line with FUT8 interference was constructed, and FUT8 knockdown decreased the adhesion of E. coli F18ac to IPEC-J2 cells (p < 0.05). Moreover, we performed a comparative transcriptome study of IPEC-J2 cells after FUT8 knockdown via RNA-seq. In addition, further expression verification demonstrated the significant effect of FUT8 on the glycosphingolipid biosynthesis and Toll-like signaling pathways. Moreover, the core promoter of FUT8, which was located at −1213 bp to −673 bp, was identified via luciferase assay. Interestingly, we found a 1 bp C base insertion mutation at the −774 bp region, which could clearly inhibit the transcriptional binding activity of C/EBPα to an FUT8 promoter. Therefore, it is speculated that FUT8 acts in a critical role in the process of E. coli infection; furthermore, the low expression of FUT8 is conducive to the enhancement of E. coli resistance in piglets. Our findings revealed the mechanism of pig FUT8 in regulating E. coli resistance, which provided a theoretical basis for the screening of E. coli resistance in Chinese local pig breeds.
Collapse
|
|
16
|
López-Cortés R, Muinelo-Romay L, Fernández-Briera A, Gil-Martín E. Inhibition of α(1,6)fucosyltransferase: Effects on Cell Proliferation, Migration, and Adhesion in an SW480/SW620 Syngeneic Colorectal Cancer Model. Int J Mol Sci 2022; 23:ijms23158463. [PMID: 35955598 PMCID: PMC9369121 DOI: 10.3390/ijms23158463] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 02/01/2023] Open
Abstract
The present study explored the impact of inhibiting α(1,6)fucosylation (core fucosylation) on the functional phenotype of a cellular model of colorectal cancer (CRC) malignization formed by the syngeneic SW480 and SW620 CRC lines. Expression of the FUT8 gene encoding α(1,6)fucosyltransferase was inhibited in tumor line SW480 by a combination of shRNA-based antisense knockdown and Lens culinaris agglutinin (LCA) selection. LCA-resistant clones were subsequently assayed in vitro for proliferation, migration, and adhesion. The α(1,6)FT-inhibited SW480 cells showed enhanced proliferation in adherent conditions, unlike their α(1,6)FT-depleted SW620 counterparts, which displayed reduced proliferation. Under non-adherent conditions, α(1,6)FT-inhibited SW480 cells also showed greater growth capacity than their respective non-targeted control (NTC) cells. However, cell migration decreased in SW480 after FUT8 knockdown, while adhesion to EA.hy926 cells was significantly enhanced. The reported results indicate that the FUT8 knockdown strategy with subsequent selection for LCA-resistant clones was effective in greatly reducing α(1,6)FT expression in SW480 and SW620 CRC lines. In addition, α(1,6)FT impairment affected the proliferation, migration, and adhesion of α(1,6)FT-deficient clones SW480 and SW620 in a tumor stage-dependent manner, suggesting that core fucosylation has a dynamic role in the evolution of CRC.
Collapse
Affiliation(s)
- Rubén López-Cortés
- Doctoral Program in Methods and Applications in Life Sciences, Faculty of Biology, Campus Lagoas-Marcosende, Universidade de Vigo, 36310 Vigo, Spain;
| | - Laura Muinelo-Romay
- Liquid Biopsy Analysis Unit, Translational Medical Oncology (Oncomet), Health Research Institute of Santiago de Compostela (IDIS), CIBERONC, Travesía da Choupana, 15706 Santiago de Compostela, Spain;
| | - Almudena Fernández-Briera
- Department of Biochemistry, Genetics and Immunology, Faculty of Biology, Campus Lagoas-Marcosende, Universidade de Vigo, 36310 Vigo, Spain;
| | - Emilio Gil-Martín
- Department of Biochemistry, Genetics and Immunology, Faculty of Biology, Campus Lagoas-Marcosende, Universidade de Vigo, 36310 Vigo, Spain;
- Correspondence: ; Tel.: +34-(986)-812-570
| |
Collapse
|
|
17
|
Kondo K, Harada Y, Nakano M, Suzuki T, Fukushige T, Hanzawa K, Yagi H, Takagi K, Mizuno K, Miyamoto Y, Taniguchi N, Kato K, Kanekura T, Dohmae N, Machida K, Maruyama I, Inoue H. Identification of distinct N-glycosylation patterns on extracellular vesicles from small-cell and non-small-cell lung cancer cells. J Biol Chem 2022; 298:101950. [PMID: 35447118 PMCID: PMC9117544 DOI: 10.1016/j.jbc.2022.101950] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/11/2022] [Accepted: 04/13/2022] [Indexed: 10/24/2022] Open
Abstract
Asparagine-linked glycosylation (N-glycosylation) of proteins in the cancer secretome has been gaining increasing attention as a potential biomarker for cancer detection and diagnosis. Small extracellular vesicles (sEVs) constitute a large part of the cancer secretome, yet little is known about whether their N-glycosylation status reflects known cancer characteristics. Here, we investigated the N-glycosylation of sEVs released from small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC) cells. We found that the N-glycans of SCLC-sEVs were characterized by the presence of structural units also found in the brain N-glycome, while NSCLC-sEVs were dominated by typical lung-type N-glycans with NSCLC-associated core fucosylation. In addition, lectin-assisted N-glycoproteomics of SCLC-sEVs and NSCLC-sEVs revealed that integrin αV was commonly expressed in sEVs of both cancer cell types, while the epithelium-specific integrin α6β4 heterodimer was selectively expressed in NSCLC-sEVs. Importantly, N-glycomics of the immuno-purified integrin α6 from NSCLC-sEVs identified NSCLC-type N-glycans on this integrin subunit. Thus, we conclude that protein N-glycosylation in lung cancer sEVs may potentially reflect the histology of lung cancers.
Collapse
Affiliation(s)
- Kiyotaka Kondo
- Department of Pulmonary Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - Yoichiro Harada
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan.
| | - Miyako Nakano
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashihiroshima 739-8530, Japan
| | - Takehiro Suzuki
- Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Tomoko Fukushige
- Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Ken Hanzawa
- Departiment of Molecular Biology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan
| | - Hirokazu Yagi
- Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
| | - Koichi Takagi
- Department of Pulmonary Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - Keiko Mizuno
- Department of Pulmonary Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - Yasuhide Miyamoto
- Departiment of Molecular Biology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan
| | - Naoyuki Taniguchi
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan
| | - Koichi Kato
- Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan; Exploratory Research Center on Life and Living Systems (ExCELLS) and Institute for Molecular Science (IMS), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan
| | - Takuro Kanekura
- Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Naoshi Dohmae
- Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Kentaro Machida
- Department of Pulmonary Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
| | - Ikuro Maruyama
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
| |
Collapse
|
|
18
|
Sun Y, Li X, Wang T, Li W. Core Fucosylation Regulates the Function of Pre-BCR, BCR and IgG in Humoral Immunity. Front Immunol 2022; 13:844427. [PMID: 35401499 PMCID: PMC8990897 DOI: 10.3389/fimmu.2022.844427] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/25/2022] [Indexed: 11/20/2022] Open
Abstract
Most of the membrane molecules involved in immune response are glycosylated. N-glycans linked to asparagine (Asn) of immune molecules contribute to the protein conformation, surface expression, stability, and antigenicity. Core fucosylation catalyzed by core fucosyltransferase (FUT8) is the most common post-translational modification. Core fucosylation is essential for evoking a proper immune response, which this review aims to communicate. First, FUT8 deficiency suppressed the interaction between μHC and λ5 during pre-BCR assembly is given. Second, we described the effects of core fucosylation in B cell signal transduction via BCR. Third, we investigated the role of core fucosylation in the interaction between helper T (TH) cells and B cells. Finally, we showed the role of FUT8 on the biological function of IgG. In this review, we discussed recent insights into the sites where core fucosylation is critical for humoral immune responses.
Collapse
Affiliation(s)
- Yuhan Sun
- College of Basic Medical Science, Dalian Medical University, Dalian, China
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, Japan
| | - Xueying Li
- Research Institute for Microbial Diseases and World Premier International Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Tiantong Wang
- College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Wenzhe Li
- College of Basic Medical Science, Dalian Medical University, Dalian, China
- *Correspondence: Wenzhe Li,
| |
Collapse
|
|
19
|
Liang Y, Wang T, Gao R, Jia X, Ji T, Shi P, Xue J, Yang A, Chen M, Han P. Fucosyltransferase 8 is Overexpressed and Influences Clinical Outcomes in Lung Adenocarcinoma Patients. Pathol Oncol Res 2022; 28:1610116. [PMID: 35237113 PMCID: PMC8883820 DOI: 10.3389/pore.2022.1610116] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 01/19/2022] [Indexed: 11/13/2022]
Abstract
Background: Lung adenocarcinoma (LUAD), the most prevalent type of lung cancer, is often metastatic and has a poor prognosis. Recent studies have demonstrated an important role for fucosyltransferase 8 (FUT8) in carcinogenesis and cancer progression. Methods: A meta-analysis with 15 eligible datasets from Gene Expression Omnibus (GEO) was performed to explore the expression of FUT8 in LUAD. The results were further verified in The Cancer Genome Atlas (TCGA) database, followed by survival analysis using Kaplan-Meier plotter. We also validated the protein expression of FUT8 by immunohistochemistry (IHC). In vitro experiments were conducted to determine the biological effects of FUT8 in LUAD cells. Results: The meta-analysis showed the FUT8 expression in LUAD tissues was significantly higher than those in normal lung tissues [standard mean difference (SMD): 1.40; 95% confidence interval (CI): .95–1.85]. The results of TCGA database verified the expression of FUT8 increased in LUAD tissues versus normal tissues. IHC analyses indicated that the protein levels of FUT8 were up-regulated in LUAD, and elevated FUT8 expression was significantly correlated with poor prognosis in LUAD patients. Multivariable Cox regression analysis revealed that FUT8 expression was an independent prognostic factor. Besides, in vitro experiments showed that knockdown of FUT8 in LUAD cells markedly restrained cell proliferation, and stimulated cell apoptosis. Conclusion: This study indicates that increased FUT8 expression is correlated with shortened survival of LUAD patients and might favor the progression of the disease.
Collapse
Affiliation(s)
- Yiqian Liang
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ting Wang
- Department of Respiratory Medicine, Xi'an No. 4 Hospital, Xi'an, China
| | - Rui Gao
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xi Jia
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ting Ji
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Puyu Shi
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jianjun Xue
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Aimin Yang
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mingwei Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Peng Han
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| |
Collapse
|
|
20
|
Zhu X, Wang X, Gong Y, Deng J. E-cadherin on epithelial-mesenchymal transition in thyroid cancer. Cancer Cell Int 2021; 21:695. [PMID: 34930256 PMCID: PMC8690896 DOI: 10.1186/s12935-021-02344-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/15/2021] [Indexed: 02/08/2023] Open
Abstract
Thyroid carcinoma is a common malignant tumor of endocrine system and head and neck. Recurrence, metastasis and high malignant expression after routine treatment are serious clinical problems, so it is of great significance to explore its mechanism and find action targets. Epithelial-mesenchymal transition (EMT) is associated with tumor malignancy and invasion. One key change in tumour EMT is low expression of E-cadherin. Therefore, this article reviews the expression of E-cadherin in thyroid cancers (TC), discuss the potential mechanisms involved, and outline opportunities to exploit E-cadherin on regulating the occurrence of EMT as a critical factor in cancer therapeutics.
Collapse
Affiliation(s)
- Xiaoyu Zhu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China
| | - Xiaoping Wang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China.
| | - Yifei Gong
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China
| | - Junlin Deng
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Jing'an District, Shanghai, 200040, China
| |
Collapse
|
|
21
|
Fan Q, Wu Y, Li M, An F, Yao L, Wang M, Wang X, Yuan J, Jiang K, Li W, Li M. Lactobacillus spp. create a protective micro-ecological environment through regulating the core fucosylation of vaginal epithelial cells against cervical cancer. Cell Death Dis 2021; 12:1094. [PMID: 34799549 PMCID: PMC8604912 DOI: 10.1038/s41419-021-04388-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 10/30/2021] [Accepted: 11/05/2021] [Indexed: 12/24/2022]
Abstract
Vaginal dysbiosis often occurs in patients with cervical cancer. The fucosylation of mucosal epithelial cells is closely related to microbial colonization, and play an important role in protecting the vaginal mucosal epithelial cells. However, no reports on the relationship between vaginal dysbiosis and abnormal mucosal epithelial cell fucosylation, and their roles in the occurrence and development of cervical cancer are unavailable. Here we report that core fucosylation levels were significantly lower in the serum, exfoliated cervical cells and tumor tissue of cervical cancer patients. Core fucosyltransferase gene (Fut8) knockout promoted the proliferation and migration of cervical cancer cells. In patients with cervical cancer, the vaginal dysbiosis, and the abundance of Lactobacillus, especially L. iners, was significantly reduced. Meanwhile, the abundance of L.iners was positively correlated with core fucosylation levels. The L. iners metabolite lactate can activate the Wnt pathway through the lactate-Gpr81 complex, which increases the level of core fucosylation in epidermal cells, inhibiting the proliferation and migration of cervical cancer cells, and have application prospects in regulating the vaginal microecology and preventing cervical cancer.
Collapse
Affiliation(s)
- Qingjie Fan
- College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Yuanhang Wu
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Mechou Li
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fan An
- The Cancer Stem Cell Research Institute of Dalian Medical University, Dalian, China
| | - Lulu Yao
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Meixian Wang
- The Reproductive and Genetics Center of Dalian Women and Children's Medical Center (Group), Dalian, China
| | - Xiuying Wang
- The Gynecology and Oncology Ward of Dalian Maternal and Child Health Hospital, Dalian, China
| | - Jieli Yuan
- College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Kui Jiang
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Wenzhe Li
- College of Basic Medical Science, Dalian Medical University, Dalian, China.
| | - Ming Li
- College of Basic Medical Science, Dalian Medical University, Dalian, China.
| |
Collapse
|
|
22
|
Ma M, Guo D, Tan Z, Du J, Guan F, Li X. Fucosyltransferase 8 regulation and breast cancer suppression by transcription factor activator protein 2γ. Cancer Sci 2021; 112:3190-3204. [PMID: 34036684 PMCID: PMC8353918 DOI: 10.1111/cas.14987] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/16/2021] [Accepted: 05/18/2021] [Indexed: 12/23/2022] Open
Abstract
Alterations of glycosyltransferase expression are often associated with tumor occurrence and progression. Among the many glycosyltransferases, increased expression of fucosyltransferase 8 (FUT8) has been frequently observed to be involved in progression and metastasis of various types of cancer. The regulatory mechanisms of FUT8 expression remain unclear. FUT8 expression was shown, in this study, to be elevated in breast cancer. Systematic analysis revealed that transcription factor activator protein 2γ (AP-2γ) is the target gene of microRNA-10b (miR-10b), which we previously identified as a positive regulator of FUT8. Overexpression of AP-2γ inhibited FUT8 expression, with associated reduction of cell invasiveness and migration ability. AP-2γ was capable of binding to transcription factor STAT3, and phosphorylation of STAT3 induced transcription of the FUT8 gene. On the basis of our findings, we propose that binding of AP-2γ to STAT3 results in formation of the AP-2γ/STAT3 complex and consequent inhibition of STAT3 phosphorylation, thereby preventing entry of p-STAT3 into the nucleus to initiate FUT8 transcription. This study clarifies the molecular mechanisms whereby transcription factor AP-2γ regulates FUT8 expression in breast cancer.
Collapse
Affiliation(s)
- Minxing Ma
- Department of Oncology, The Fifth People's Hospital of Qinghai Province, Xining, China
| | - Dong Guo
- Department of Central Lab, Cheeloo College of Medicine, Weihai Municipal Hospital, Shandong University, Weihai, China
| | - Zengqi Tan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Sciences, Northwest University, Xi'an, China
| | - Jun Du
- Department of Oncology, The Fifth People's Hospital of Qinghai Province, Xining, China
| | - Feng Guan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Sciences, Northwest University, Xi'an, China
| | - Xiang Li
- Institute of Hematology, School of Medicine, Northwest University, Xi'an, China
| |
Collapse
|
|
23
|
Liao C, An J, Yi S, Tan Z, Wang H, Li H, Guan X, Liu J, Wang Q. FUT8 and Protein Core Fucosylation in Tumours: From Diagnosis to Treatment. J Cancer 2021; 12:4109-4120. [PMID: 34093814 PMCID: PMC8176256 DOI: 10.7150/jca.58268] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023] Open
Abstract
Glycosylation changes are key molecular events in tumorigenesis, progression and glycosyltransferases play a vital role in the this process. FUT8 belongs to the fucosyltransferase family and is the key enzyme involved in N-glycan core fucosylation. FUT8 and/or core fucosylated proteins are frequently upregulated in liver, lung, colorectal, pancreas, prostate,breast, oral cavity, oesophagus, and thyroid tumours, diffuse large B-cell lymphoma, ependymoma, medulloblastoma and glioblastoma multiforme and downregulated in gastric cancer. They can be used as markers of cancer diagnosis, occurrence, progression and prognosis. Core fucosylated EGFR, TGFBR, E-cadherin, PD1/PD-L1 and α3β1 integrin are potential targets for tumour therapy. In addition, IGg1 antibody defucosylation can improve antibody affinity, which is another aspect of FUT8 that could be applied to tumour therapy.
Collapse
Affiliation(s)
- Chengcheng Liao
- Special Key Laboratory of Oral Disease Research, Higher Education Institution in Guizhou Province, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Jiaxing An
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Suqin Yi
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Zhangxue Tan
- Special Key Laboratory of Oral Disease Research, Higher Education Institution in Guizhou Province, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Hui Wang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Hao Li
- Special Key Laboratory of Oral Disease Research, Higher Education Institution in Guizhou Province, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Xiaoyan Guan
- Department of Orthodontics II, Hospital of Stomatology, Zunyi Medical University, Zunyi 563000, China
| | - Jianguo Liu
- Special Key Laboratory of Oral Disease Research, Higher Education Institution in Guizhou Province, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Qian Wang
- Special Key Laboratory of Oral Disease Research, Higher Education Institution in Guizhou Province, School of Stomatology, Zunyi Medical University, Zunyi 563006, China.,Microbial Resources and Drug Development Key Laboratory of Guizhou Tertiary Institution, Life Sciences Institute, Zunyi Medical University, Zunyi 563006, China
| |
Collapse
|
|
24
|
Benchmark of site- and structure-specific quantitative tissue N-glycoproteomics for discovery of potential N-glycoprotein markers: a case study of pancreatic cancer. Glycoconj J 2021; 38:213-231. [PMID: 33835347 DOI: 10.1007/s10719-021-09994-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 03/16/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is a highly malignant tumor of the digestive tract that is difficult to diagnose and treat. It is more common in developed countries and has become one of the main causes of death in some countries and regions. Currently, pancreatic cancer generally has a poor prognosis, partly due to the lack of symptoms in the early stages of pancreatic cancer. Therefore, most cases are diagnosed at advanced stage. With the continuous in-depth research of glycoproteomics in precision medical diagnosis, there have been some reports on quantitative analysis of cancer-related cells, plasma or tissues to find specific biomarkers for targeted therapy. This research is based on the developed complete N-linked glycopeptide database search engine GPSeeker, combined with liquid-mass spectrometry and stable diethyl isotope labeling, providing a benchmark of site- and structure-specific quantitative tissue N-glycoproteomics for discovery of potential N-glycoprotein markers. With spectrum-level FDR ≤1%, 20,038 intact N-Glycopeptides corresponding to 4518 peptide backbones, 228 N-glycan monosaccharide compositions 1026 N-glycan putative structures, 4460 N-glycosites and 3437 intact N-glycoproteins were identified. With the criteria of ≥1.5-fold change and p value<0.05, 52 differentially expressed intact N-glycopeptides (DEGPs) were found in pancreatic cancer tussues relative to control, where 38 up-regulated and 14 down-regulated, respectively.
Collapse
|
|
25
|
Ohkawa Y, Harada Y, Taniguchi N. Keratan sulfate-based glycomimetics using Langerin as a target for COPD: lessons from studies on Fut8 and core fucose. Biochem Soc Trans 2021; 49:441-453. [PMID: 33616615 PMCID: PMC7924997 DOI: 10.1042/bst20200780] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/14/2021] [Accepted: 01/29/2021] [Indexed: 12/19/2022]
Abstract
Glycosylation represents one of the most abundant posttranslational modification of proteins. Glycosylation products are diverse and are regulated by the cooperative action of various glycosyltransferases, glycosidases, substrates thereof: nucleoside sugars and their transporters, and chaperons. In this article, we focus on a glycosyltransferase, α1,6-fucosyltransferase (Fut8) and its product, the core fucose structure on N-glycans, and summarize the potential protective functions of this structure against emphysema and chronic obstructive pulmonary disease (COPD). Studies of FUT8 and its enzymatic product, core fucose, are becoming an emerging area of interest in various fields of research including inflammation, cancer and therapeutics. This article discusses what we can learn from studies of Fut8 and core fucose by using knockout mice or in vitro studies that were conducted by our group as well as other groups. We also include a discussion of the potential protective functions of the keratan sulfate (KS) disaccharide, namely L4, against emphysema and COPD as a glycomimetic. Glycomimetics using glycan analogs is one of the more promising therapeutics that compensate for the usual therapeutic strategy that involves targeting the genome and the proteome. These typical glycans using KS derivatives as glycomimetics, will likely become a clue to the development of novel and effective therapeutic strategies.
Collapse
MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, Surface/genetics
- Antigens, Surface/metabolism
- Antigens, Surface/physiology
- Biomimetic Materials/chemistry
- Biomimetic Materials/therapeutic use
- Fucose/metabolism
- Fucosyltransferases/physiology
- Glycosylation
- Humans
- Keratan Sulfate/chemistry
- Lectins, C-Type/antagonists & inhibitors
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Lectins, C-Type/physiology
- Mannose-Binding Lectins/antagonists & inhibitors
- Mannose-Binding Lectins/genetics
- Mannose-Binding Lectins/metabolism
- Mannose-Binding Lectins/physiology
- Mice
- Mice, Knockout
- Molecular Targeted Therapy/methods
- Polysaccharides/chemistry
- Polysaccharides/metabolism
- Pulmonary Disease, Chronic Obstructive/drug therapy
- Pulmonary Disease, Chronic Obstructive/genetics
- Pulmonary Disease, Chronic Obstructive/metabolism
Collapse
Affiliation(s)
- Yuki Ohkawa
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan
| | - Yoichiro Harada
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan
| | - Naoyuki Taniguchi
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan
| |
Collapse
|
|
26
|
Bastian K, Scott E, Elliott DJ, Munkley J. FUT8 Alpha-(1,6)-Fucosyltransferase in Cancer. Int J Mol Sci 2021; 22:E455. [PMID: 33466384 PMCID: PMC7795606 DOI: 10.3390/ijms22010455] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/21/2020] [Accepted: 12/24/2020] [Indexed: 12/15/2022] Open
Abstract
Aberrant glycosylation is a universal feature of cancer cells that can impact all steps in tumour progression from malignant transformation to metastasis and immune evasion. One key change in tumour glycosylation is altered core fucosylation. Core fucosylation is driven by fucosyltransferase 8 (FUT8), which catalyses the addition of α1,6-fucose to the innermost GlcNAc residue of N-glycans. FUT8 is frequently upregulated in cancer, and plays a critical role in immune evasion, antibody-dependent cellular cytotoxicity (ADCC), and the regulation of TGF-β, EGF, α3β1 integrin and E-Cadherin. Here, we summarise the role of FUT8 in various cancers (including lung, liver, colorectal, ovarian, prostate, breast, melanoma, thyroid, and pancreatic), discuss the potential mechanisms involved, and outline opportunities to exploit FUT8 as a critical factor in cancer therapeutics in the future.
Collapse
Affiliation(s)
- Kayla Bastian
- Institute of Biosciences, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK; (E.S.); (D.J.E.); (J.M.)
| | | | | | | |
Collapse
|
|
27
|
Fernandes Â, Dias AM, Silva MC, Gaifem J, Azevedo CM, Carballo I, Pinho SS. The Role of Glycans in Chronic Inflammatory Gastrointestinal and Liver Disorders and Cancer. COMPREHENSIVE GLYCOSCIENCE 2021:444-470. [DOI: 10.1016/b978-0-12-819475-1.00036-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
28
|
Ma M, Han G, Wang Y, Zhao Z, Guan F, Li X. Role of FUT8 expression in clinicopathology and patient survival for various malignant tumor types: a systematic review and meta-analysis. Aging (Albany NY) 2020; 13:2212-2230. [PMID: 33323540 PMCID: PMC7880376 DOI: 10.18632/aging.202239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 10/22/2020] [Indexed: 12/28/2022]
Abstract
Dysregulation of α(1,6)-fucosyltransferase (FUT8) plays significant roles in development of a variety of malignant tumor types. We collected as many relevant articles and microarray datasets as possible to assess the prognostic value of FUT8 expression in malignant tumors. For this purpose, we systematically searched PubMed, Embase, Web of Science, Springer, Chinese National Knowledge Infrastructure (CNKI), and Wan Fang, and eventually identified 7 articles and 35 microarray datasets (involving 6124 patients and 10 tumor types) for inclusion in meta-analysis. In each tumor type, FUT8 expression showed significant (p< 0.05) correlation with one or more clinicopathological parameters; these included patient gender, molecular subgroup, histological grade, TNM stage, estrogen receptor, progesterone receptor, and recurrence status. In regard to survival prognosis, FUT8 expression level was associated with overall survival in non-small cell lung cancer (NSCLC), breast cancer, diffuse large B cell lymphoma, gastric cancer, and glioma. FUT8 expression was also correlated with disease-free survival in NSCLC, breast cancer, and colorectal cancer, and with relapse-free survival in pancreatic ductal adenocarcinoma. For most tumor types, survival prognosis of patients with high FUT8 expression was related primarily to clinical features such as gender, tumor stage, age, and pathological category. Our systematic review and meta-analysis confirmed the association of FUT8 with clinicopathological features and patient survival rates for numerous malignant tumor types. Verification of prognostic value of FUT8 in these tumor types will require a large-scale study using standardized methods of detection and analysis.
Collapse
Affiliation(s)
- Minxing Ma
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Institute of Hematology, School of Medicine, Northwest University, Xi'an, China.,Department of Oncology, The Fifth People's Hospital of Qinghai Province, Xining, China
| | - Guoxiong Han
- Department of Oncology, The Fifth People's Hospital of Qinghai Province, Xining, China
| | - Yi Wang
- Department of Hematology, Provincial People's Hospital, Xi'an, Shaanxi, China
| | - Ziyan Zhao
- Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, Xi'an, China
| | - Feng Guan
- Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, Xi'an, China
| | - Xiang Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Institute of Hematology, School of Medicine, Northwest University, Xi'an, China.,Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Science, Northwest University, Xi'an, China
| |
Collapse
|
|
29
|
Thomas D, Rathinavel AK, Radhakrishnan P. Altered glycosylation in cancer: A promising target for biomarkers and therapeutics. Biochim Biophys Acta Rev Cancer 2020; 1875:188464. [PMID: 33157161 DOI: 10.1016/j.bbcan.2020.188464] [Citation(s) in RCA: 189] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 10/08/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022]
Abstract
Glycosylation is a well-regulated cell and microenvironment specific post-translational modification. Several glycosyltransferases and glycosidases orchestrate the addition of defined glycan structures on the proteins and lipids. Recent advances and systemic approaches in glycomics have significantly contributed to a better understanding of instrumental roles of glycans in health and diseases. Emerging research evidence recognized aberrantly glycosylated proteins as the modulators of the malignant phenotype of cancer cells. The Cancer Genome Atlas has identified alterations in the expressions of glycosylation-specific genes that are correlated with cancer progression. However, the mechanistic basis remains poorly explored. Recent researches have shown that specific changes in the glycan structures are associated with 'stemness' and epithelial-to-mesenchymal transition of cancer cells. Moreover, epigenetic changes in the glycosylation pattern make the tumor cells capable of escaping immunosurveillance mechanisms. The deciphering roles of glycans in cancer emphasize that glycans can serve as a source for the development of novel clinical biomarkers. The ability of glycans in intervening various stages of tumor progression and the biosynthetic pathways involved in glycan structures constitute a promising target for cancer therapy. Advances in the knowledge of innovative strategies for identifying the mechanisms of glycan-binding proteins are hoped to hold great potential in cancer therapy. This review discusses the fundamental role of glycans in regulating tumorigenesis and tumor progression and provides insights into the influence of glycans in the current tactics of targeted therapies in the clinical setting.
Collapse
Affiliation(s)
- Divya Thomas
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ashok Kumar Rathinavel
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Prakash Radhakrishnan
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| |
Collapse
|
|
30
|
Taniguchi N, Ohkawa Y, Maeda K, Harada Y, Nagae M, Kizuka Y, Ihara H, Ikeda Y. True significance of N-acetylglucosaminyltransferases GnT-III, V and α1,6 fucosyltransferase in epithelial-mesenchymal transition and cancer. Mol Aspects Med 2020; 79:100905. [PMID: 33010941 DOI: 10.1016/j.mam.2020.100905] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 09/02/2020] [Indexed: 12/13/2022]
Abstract
It is well known that numerous cancer-related changes occur in glycans that are attached to glycoproteins, glycolipids and proteoglycans on the cell surface and these changes in structure and the expression of the glycans are largely regulated by glycosyl-transferases, glycosidases, nucleotide sugars and their related genes. Such structural changes in glycans on cell surface proteins may accelerate the progression, invasion and metastasis of cancer cells. Among the over 200 known glycosyltransferases and related genes, β 1,6 N-acetylglucosaminyltransferase V (GnT-V) (the MGAT5 gene) and α 1,6 fucosyltransferase (FUT8) (the FUT8 gene) are representative enzymes in this respect because changes in glycans caused by these genes appear to be related to cancer metastasis and invasion in vitro as well as in vivo, and a number of reports on these genes in related to epithelial-mesenchymal transition (EMT) have also appeared. Another enzyme, one of the N-glycan branching enzymes, β1,4 N-acetylglucosaminyltransferase III (GnT-III) (the MGAT3 gene) has been reported to suppress EMT. However, there are intermediate states between EMT and mesenchymal-epithelial transition (MET) and some of these genes have been implicated in both EMT and MET and are also probably in an intermediate state. Therefore, it would be difficult to clearly define which specific glycosyltransferase is involved in EMT or MET or an intermediate state. The significance of EMT and N-glycan branching glycosyltransferases needs to be reconsidered and the inhibition of their corresponding genes would also be desirable in therapeutics. This review mainly focuses on GnT-III, GnT-V and FUT8, major players as N-glycan branching enzymes in cancer in relation to EMT programs, and also discusses the catalytic mechanisms of GnT-V and FUT8 whose crystal structures have now been obtained.
Collapse
Affiliation(s)
- Naoyuki Taniguchi
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka, Japan.
| | - Yuki Ohkawa
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka, Japan.
| | - Kento Maeda
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka, Japan.
| | - Yoichiro Harada
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka, Japan.
| | - Masamichi Nagae
- Department of Molecular Immunology, RIMD, Osaka University, Osaka, Japan.
| | - Yasuhiko Kizuka
- Glyco-biochemistry Laboratory, G-Chain, Gifu University, Gifu, Japan.
| | - Hideyuki Ihara
- Division of Molecular Cell Biology, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan.
| | - Yoshitaka Ikeda
- Division of Molecular Cell Biology, Department of Biomolecular Sciences, Saga University Faculty of Medicine, Saga, Japan.
| |
Collapse
|
|
31
|
Soroko M, Kwan DH. Enzymatic Synthesis of a Fluorogenic Reporter Substrate and the Development of a High-Throughput Assay for Fucosyltransferase VIII Provide a Toolkit to Probe and Inhibit Core Fucosylation. Biochemistry 2020; 59:2100-2110. [PMID: 32441090 DOI: 10.1021/acs.biochem.0c00286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Maxim Soroko
- Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montreal, Quebec, Canada H4B 1R6
| | - David H. Kwan
- Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montreal, Quebec, Canada H4B 1R6
- Department of Biology, Centre for Applied Synthetic Biology, and Centre for Structural and Functional Genomics, Concordia University, 7141 Sherbrooke Street West, Montreal, Quebec, Canada H4B 1R6
| |
Collapse
|
|
32
|
Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase. Nat Commun 2020; 11:973. [PMID: 32080177 PMCID: PMC7033129 DOI: 10.1038/s41467-020-14794-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 01/30/2020] [Indexed: 12/22/2022] Open
Abstract
Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the only enzyme responsible for this modification via the addition of an α-1,6-linked fucose to N-glycans. To date, the details of substrate recognition and catalysis by FUT8 remain unknown. Here, we report the crystal structure of FUT8 complexed with GDP and a biantennary complex N-glycan (G0), which provides insight into both substrate recognition and catalysis. FUT8 follows an SN2 mechanism and deploys a series of loops and an α-helix which all contribute in forming the binding site. An exosite, formed by one of these loops and an SH3 domain, is responsible for the recognition of branched sugars, making contacts specifically to the α1,3 arm GlcNAc, a feature required for catalysis. This information serves as a framework for inhibitor design, and helps to assess its potential as a therapeutic target.
Collapse
|
|
33
|
Höti N, Lih TS, Pan J, Zhou Y, Yang G, Deng A, Chen L, Dong M, Yang RB, Tu CF, Haffner MC, Kay Li Q, Zhang H. A Comprehensive Analysis of FUT8 Overexpressing Prostate Cancer Cells Reveals the Role of EGFR in Castration Resistance. Cancers (Basel) 2020; 12:cancers12020468. [PMID: 32085441 PMCID: PMC7072180 DOI: 10.3390/cancers12020468] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/03/2020] [Accepted: 02/10/2020] [Indexed: 01/12/2023] Open
Abstract
The emergence of castration-resistance is one of the major challenges in the management of patients with advanced prostate cancer. Although the spectrum of systemic therapies that are available for use alongside androgen deprivation for treatment of castration-resistant prostate cancer (CRPC) is expanding, none of these regimens are curative. Therefore, it is imperative to apply systems approaches to identify and understand the mechanisms that contribute to the development of CRPC. Using comprehensive proteomic approaches, we show that a glycosylation-related enzyme, alpha (1,6) fucosyltransferase (FUT8), which is upregulated in CRPC, might be responsible for resistance to androgen deprivation. Mechanistically, we demonstrated that overexpression of FUT8 resulted in upregulation of the cell surface epidermal growth factor receptor (EGFR) and corresponding downstream signaling, leading to increased cell survival in androgen-depleted conditions. We studied the coregulatory mechanisms of EGFR and FUT8 expression in CRPC xenograft models and found that castration induced FUT8 overexpression associated with increased expression of EGFR. Taken together, our findings suggest a crucial role played by FUT8 as a mediator in switching prostate cancer cells from nuclear receptor signaling (androgen receptor) to the cell surface receptor (EGFR) mechanisms in escaping castration-induced cell death. These findings have clinical implication in understanding the role of FUT8 as a master regulator of cell surface receptors in cancer-resistant phenotypes.
Collapse
Affiliation(s)
- Naseruddin Höti
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.-S.L.); (J.P.); (Y.Z.); (G.Y.); (A.D.); (L.C.); (M.D.); (M.C.H.); (Q.K.L.); (H.Z.)
- Correspondence: ; Tel.: (410)-502-8149; Fax: (443)-287-6388
| | - Tung-Shing Lih
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.-S.L.); (J.P.); (Y.Z.); (G.Y.); (A.D.); (L.C.); (M.D.); (M.C.H.); (Q.K.L.); (H.Z.)
| | - Jianbo Pan
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.-S.L.); (J.P.); (Y.Z.); (G.Y.); (A.D.); (L.C.); (M.D.); (M.C.H.); (Q.K.L.); (H.Z.)
| | - Yangying Zhou
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.-S.L.); (J.P.); (Y.Z.); (G.Y.); (A.D.); (L.C.); (M.D.); (M.C.H.); (Q.K.L.); (H.Z.)
| | - Ganglong Yang
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.-S.L.); (J.P.); (Y.Z.); (G.Y.); (A.D.); (L.C.); (M.D.); (M.C.H.); (Q.K.L.); (H.Z.)
| | - Ashely Deng
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.-S.L.); (J.P.); (Y.Z.); (G.Y.); (A.D.); (L.C.); (M.D.); (M.C.H.); (Q.K.L.); (H.Z.)
| | - Lijun Chen
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.-S.L.); (J.P.); (Y.Z.); (G.Y.); (A.D.); (L.C.); (M.D.); (M.C.H.); (Q.K.L.); (H.Z.)
| | - Mingmimg Dong
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.-S.L.); (J.P.); (Y.Z.); (G.Y.); (A.D.); (L.C.); (M.D.); (M.C.H.); (Q.K.L.); (H.Z.)
| | - Ruey-Bing Yang
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; (R.-B.Y.); (C.-F.T.)
| | - Cheng-Fen Tu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; (R.-B.Y.); (C.-F.T.)
| | - Michael C. Haffner
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.-S.L.); (J.P.); (Y.Z.); (G.Y.); (A.D.); (L.C.); (M.D.); (M.C.H.); (Q.K.L.); (H.Z.)
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Qing Kay Li
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.-S.L.); (J.P.); (Y.Z.); (G.Y.); (A.D.); (L.C.); (M.D.); (M.C.H.); (Q.K.L.); (H.Z.)
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Hui Zhang
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.-S.L.); (J.P.); (Y.Z.); (G.Y.); (A.D.); (L.C.); (M.D.); (M.C.H.); (Q.K.L.); (H.Z.)
| |
Collapse
|
|
34
|
Tada K, Ohta M, Hidano S, Watanabe K, Hirashita T, Oshima Y, Fujnaga A, Nakanuma H, Masuda T, Endo Y, Takeuchi Y, Iwashita Y, Kobayashi T, Inomata M. Fucosyltransferase 8 plays a crucial role in the invasion and metastasis of pancreatic ductal adenocarcinoma. Surg Today 2020; 50:767-777. [PMID: 31950256 DOI: 10.1007/s00595-019-01953-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 12/03/2019] [Indexed: 12/29/2022]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. It is an aggressive malignancy associated with poor prognosis because of recurrence, metastasis, and treatment resistance. Aberrant glycosylation of cancer cells triggers their migration and invasion and is considered one of the most important prognostic cancer biomarkers. The current study aimed to identify glycan alterations and their relationship with the malignant potential of PDAC. METHODS Using a lectin microarray, we evaluated glycan expression in 62 PDAC samples. Expression of fucosyltransferase 8 (FUT8), the only enzyme catalyzing core fucosylation, was investigated by immunohistochemistry. The role of FUT8 in PDAC invasion and metastasis was confirmed using an in vitro assay and a xenograft peritoneal metastasis mouse model. RESULTS The microarray data demonstrated that core fucose-binding lectins were significantly higher in carcinoma than in normal pancreatic duct tissues. Similarly, FUT8 protein expression was significantly higher in carcinoma than in normal pancreatic duct tissues. High FUT8 protein expression was significantly associated with lymph-node metastases and relapse-free survival. FUT8 knockdown significantly reduced the invasion in PDAC cell lines and impaired peritoneal metastasis in the xenograft model. CONCLUSIONS The findings of this study provide evidence that FUT8 plays a pivotal role in PDAC invasion and metastasis and might be a therapeutic target for this disease.
Collapse
Affiliation(s)
- Kazuhiro Tada
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan.
| | - Masayuki Ohta
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan.,Global Oita Medical Advanced Research Center for Health, Oita University, Oita, Japan
| | - Shinya Hidano
- Department of Infectious Disease Control, Faculty of Medicine, Oita University, Oita, Japan
| | - Kiminori Watanabe
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Teijiro Hirashita
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Yusuke Oshima
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan.,Biomedical Optics Laboratory, Graduate School of Biomedical Engineering Tohoku University, Miyagi, Japan.,Oral-Maxillofacial Surgery and Orthodontics, University of Tokyo Hospital, Tokyo, Japan
| | - Atsuro Fujnaga
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Hiroaki Nakanuma
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Takashi Masuda
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Yuichi Endo
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Yu Takeuchi
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Yukio Iwashita
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| | - Takashi Kobayashi
- Department of Infectious Disease Control, Faculty of Medicine, Oita University, Oita, Japan
| | - Masafumi Inomata
- Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita, 879-5593, Japan
| |
Collapse
|
|
35
|
Keeley TS, Yang S, Lau E. The Diverse Contributions of Fucose Linkages in Cancer. Cancers (Basel) 2019; 11:E1241. [PMID: 31450600 PMCID: PMC6769556 DOI: 10.3390/cancers11091241] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Revised: 08/12/2019] [Accepted: 08/20/2019] [Indexed: 12/17/2022] Open
Abstract
Fucosylation is a post-translational modification of glycans, proteins, and lipids that is responsible for many biological processes. Fucose conjugation via α(1,2), α(1,3), α(1,4), α(1,6), and O'- linkages to glycans, and variations in fucosylation linkages, has important implications for cancer biology. This review focuses on the roles that fucosylation plays in cancer, specifically through modulation of cell surface proteins and signaling pathways. How L-fucose and serum fucosylation patterns might be used for future clinical diagnostic, prognostic, and therapeutic approaches will be discussed.
Collapse
Affiliation(s)
- Tyler S Keeley
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
- University of South Florida Cancer Biology Graduate Program, Tampa, FL 33602, USA
- Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL 33602, USA
| | - Shengyu Yang
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA.
| | - Eric Lau
- Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL 33602, USA.
| |
Collapse
|
|
36
|
Ma M, Fu Y, Zhou X, Guan F, Wang Y, Li X. Functional roles of fucosylated and O-glycosylated cadherins during carcinogenesis and metastasis. Cell Signal 2019; 63:109365. [PMID: 31352008 DOI: 10.1016/j.cellsig.2019.109365] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/24/2019] [Accepted: 07/24/2019] [Indexed: 12/30/2022]
Abstract
Reduced cellular adhesiveness as a result of cadherin dysfunction is a defining feature of cancer and the mechanism involved in many aspects. Glycosylation is one of the most important post-translational modifications to cadherin. Major changes of glycosylation on cadherins can affect its stability, trafficking, and cell-adhesion properties. It has been reported that the different glycoforms of cadherins are promising biomarkers in cancer, with potential clinical application to constitute targets for the development of new therapies. Among the various glycoforms of cadherins, fucosylated and O-glycosylated cadherins are attracting more attention for their important roles in regulating cadherin functions during carcinogenesis. This review will discuss the most recent insights of the functional roles of fucosylated and O-glycosylated cadherins and their regulation mechanisms during carcinogenesis and metastasis. In summary, more understanding of fucosylated and O-glycosylated cadherins will lead to development of novel therapeutic approaches targeted to cancer.
Collapse
Affiliation(s)
- Minxing Ma
- Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Sciences, Northwest University, Xi'an, China; Department of Oncology, the Fifth People's Hospital of Qinghai Province, Xining, China
| | - Yutong Fu
- Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Sciences, Northwest University, Xi'an, China
| | - Xiaoman Zhou
- The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, China
| | - Feng Guan
- Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Sciences, Northwest University, Xi'an, China
| | - Yi Wang
- Department of Hematology, Provincial People's Hospital, Xi'an, China.
| | - Xiang Li
- Joint International Research Laboratory of Glycobiology and Medicinal Chemistry, College of Life Sciences, Northwest University, Xi'an, China; Wuxi School of Medicine, Jiangnan University, Wuxi, China.
| |
Collapse
|
|
37
|
Penezić A, Križakova M, Miljuš G, Katrlik J, Nedić O. Diagnostic Potential of Transferrin Glycoforms-A Lectin-Based Protein Microarray Approach. Proteomics Clin Appl 2019; 13:e1800185. [PMID: 31050875 DOI: 10.1002/prca.201800185] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/28/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE Disease or a specific condition may cause alteration of human transferrin (hTf) glycosylation pattern. A specific analytical platform, lectin-based protein microarray, is designed and optimized for the investigation of hTf glycans, attached to the protein core in their native form. EXPERIMENTAL DESIGN hTf molecules isolated from healthy persons of different age, diabetes mellitus type 2 (T2DM) or colorectal carcinoma (CRC) patients are used for method validation. Reliability of the results is ensured by three criteria for the evaluation of hTf-lectin interactions: i) signal-to-noise ratio above 3, ii) signal intensity above 250 arbitrary units, and iii) hTf concentration ensuring high sensitivity of the assay. RESULTS Six lectins, out of fourteen tested, satisfy the criteria. hTf is spotted at concentration of 50 µg mL-L . When physiological samples (isolated hTf) are analyzed, the highest potential to differentiate between population groups expresses Aleuria aurantia (AAL), Triticum vulgaris (WGA) and Phaseolus vulgaris (PHA-E) lectins. The initial amount of hTf which can be analyzed is very low (75 pg). CONCLUSION AND CLINICAL RELEVANCE Results confirm that a very sensitive, high-throughput lectin-based protein microarray platform can be formulated to detect changes in hTf glycan structures which can be considered as biomarkers of ageing or a disease.
Collapse
Affiliation(s)
- Ana Penezić
- Institute for the Application of Nuclear Energy (INEP), Banatska 31b, 11080, Belgrade, Serbia
| | - Martina Križakova
- Slovak Academy of Sciences, Dúbravská cesta 9, 845 38, Bratislava, Slovak Republic
| | - Goran Miljuš
- Institute for the Application of Nuclear Energy (INEP), Banatska 31b, 11080, Belgrade, Serbia
| | - Jaroslav Katrlik
- Slovak Academy of Sciences, Dúbravská cesta 9, 845 38, Bratislava, Slovak Republic
| | - Olgica Nedić
- Institute for the Application of Nuclear Energy (INEP), Banatska 31b, 11080, Belgrade, Serbia
| |
Collapse
|
|
38
|
Harada Y, Kizuka Y, Tokoro Y, Kondo K, Yagi H, Kato K, Inoue H, Taniguchi N, Maruyama I. N-glycome inheritance from cells to extracellular vesicles in B16 melanomas. FEBS Lett 2019; 593:942-951. [PMID: 30943309 PMCID: PMC6594130 DOI: 10.1002/1873-3468.13377] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/20/2019] [Accepted: 04/01/2019] [Indexed: 01/09/2023]
Abstract
We investigated the correlation between metastatic behaviors of tumor cells and asparagine‐linked glycosylation (N‐glycosylation) of tumor‐derived extracellular vesicles (EVs). Three mouse melanoma B16 variants with distinct metastatic potentials show similar gene expression levels and enzymatic activities of glycosyltransferases involved in N‐glycosylation. All melanoma variants and EVs have nearly identical profiles of de‐sialylated N‐glycans. The major de‐sialylated N‐glycan structures of cells and EVs are core‐fucosylated, tetra‐antennary N‐glycans with β1,6‐N‐acetylglucosamine branches. A few N‐glycans are extended by N‐acetyllactosamine repeats. Sialylation of these N‐glycans may generate cell‐type‐specific N‐glycomes on EVs. Taken together, melanoma‐derived EVs show high expression of tumor‐associated N‐glycans, and the core structure profile is inherited during multiple selection cycles of B16 melanomas and from tumor cells to EVs.
Collapse
Affiliation(s)
- Yoichiro Harada
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
| | - Yasuhiko Kizuka
- Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Japan
| | - Yuko Tokoro
- Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Japan
| | - Kiyotaka Kondo
- Department of Pulmonary Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
| | - Hirokazu Yagi
- Graduate School of Pharmaceutical Sciences, Nagoya City University, Japan
| | - Koichi Kato
- Graduate School of Pharmaceutical Sciences, Nagoya City University, Japan.,Exploratory Research Center on Life and Living Systems (ExCELLS), Institute for Molecular Science (IMS), National Institutes of Natural Sciences, Okazaki, Japan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
| | - Naoyuki Taniguchi
- Department of Glyco-Oncology, Osaka International Cancer Institute, Japan
| | - Ikuro Maruyama
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
| |
Collapse
|
|
39
|
Shan M, Yang D, Dou H, Zhang L. Fucosylation in cancer biology and its clinical applications. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2019; 162:93-119. [PMID: 30905466 DOI: 10.1016/bs.pmbts.2019.01.002] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Fucosylation is the process of transferring fucose from GDP-fucose to their substrates, which includes certain proteins, N- and O-linked glycans in glycoprotein or glycolipids, by fucosyltransferases in all mammalian cells. Fucosylated glycans play vital role in selectin-mediated leukocyte extravasation, lymphocyte homing, and pathogen-host interactions, whereas fucosylated proteins are essential for signaling transduction in numerous ontogenic events. Aberrant fucosylation due to the availability of high energy donor GDP-fucose, abnormal expression of FUTs and/or α-fucosidase, and the availability of their substrates leads to different fucosylated glycan or protein structures. Accumulating evidence demonstrates that aberrant fucosylation plays important role in all aspects of cancer biology. In this review, we will summarize the current knowledge about fucosylation in different physiological and pathological processes with a focus on their roles not only in cancer cell proliferation, invasion, and metastasis but also in tumor immune surveillance. Furthermore, the clinical potential and applications of fucosylation in cancer diagnosis and treatment will also be discussed.
Collapse
Affiliation(s)
- Ming Shan
- Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Dandan Yang
- Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Huaiqian Dou
- Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lijuan Zhang
- Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China.
| |
Collapse
|
|
40
|
Nakayama K, Wakamatsu K, Fujii H, Shinzaki S, Takamatsu S, Kitazume S, Kamada Y, Takehara T, Taniguchi N, Miyoshi E. Core fucose is essential glycosylation for CD14-dependent Toll-like receptor 4 and Toll-like receptor 2 signalling in macrophages. J Biochem 2019; 165:227-237. [PMID: 30445455 DOI: 10.1093/jb/mvy098] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 11/13/2018] [Indexed: 02/09/2025] Open
Abstract
Core fucosylation, catalysed by α-1, 6 fucosyltransferase (FUT8), regulates growth factor receptors in immune function. Although core fucose regulates many immune cell types, few reports confront the association between core fucose activity and an innate immune reaction. Here, we have investigated the function of core fucose in macrophages in vivo and in vitro using Fut8-deficient mice and cells. Following lipopolysaccharide (LPS) stimulation, inflammatory cytokine production in Fut8-deficient (Fut8-/-) macrophages was suppressed in both in vivo and in vitro experiments. Because LPS is recognized by Toll-like receptor 4 (TLR4), which induces the signalling cascade, TLR4 signalling was assumed to be impaired in Fut8-/- cells. Flow cytometry analyses revealed, however, that a lack of core fucose reduced the expression of, not TLR4, but CD14, which is necessary for TLR4 endocytosis. Because CD14 is necessary for TLR2 signalling, the immune response of TLR2 was also impaired in Fut8-/- macrophages. Moreover, in the dextran sodium sulphate (DSS)-induced murine colitis model, the mice grafted with Fut8-/- bone marrow cells exhibited higher resistance to inflammation than those grafted with Fut8+/+ bone marrow cells. These findings indicate that core fucose is essential for CD14-dependent TLR4 and TLR2 signalling in murine macrophage activity, leading to DSS-induced experimental colitis.
Collapse
Affiliation(s)
| | - Kana Wakamatsu
- Department of Molecular Biochemistry and Clinical Investigation
| | - Hironobu Fujii
- Department of Molecular Biochemistry and Clinical Investigation
| | - Shinichiro Shinzaki
- Department of Molecular Biochemistry and Clinical Investigation
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | | | - Shinobu Kitazume
- Disease Glycomics Team, Systems Glycobiology Research Group, RIKEN, Saitama, Japan
| | - Yoshihiro Kamada
- Department of Molecular Biochemistry and Clinical Investigation
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naoyuki Taniguchi
- Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation
| |
Collapse
|
|
41
|
Abstract
Hypoxia, a common condition of the tumor microenvironment, induces changes in the proteome of cancer cells, mainly via HIF-1, a transcription factor conformed by a constitutively expressed β-subunit and an oxygen-regulated α-subunit. In hypoxia, HIF-1α stabilizes, forms the heterodimeric complex with HIF-1β, and binds to Hypoxia Response Elements (HRE), activating gene expression to promote metabolic adaptation, cell invasion and metastasis. Furthermore, the focal adhesion kinase, FAK, is activated in hypoxia, promoting cell migration by mechanisms that remain unclear. In this context, integrins, which are glycoproteins required for cell migration, are possibly involved in hypoxia-induced FAK activation. Evidence suggests that cancer cells have an altered glycosylation metabolism, mostly by the expression of glycosyltransferases, however the relevance of glycosylation is poorly explored in the context of hypoxia. Here, we discuss the role of hypoxia in cancer, and its effects on protein glycosylation, with emphasis on integrins and cell migration.
Collapse
Affiliation(s)
- Cecilia Arriagada
- a Institute for Research in Dental Sciences, Faculty of Dentistry , Universidad de Chile , Santiago , Chile.,b School of Pedagogy in Physical Education, Sports and Recreation , Universidad Bernardo O'Higgins , Santiago , Chile
| | - Patricio Silva
- a Institute for Research in Dental Sciences, Faculty of Dentistry , Universidad de Chile , Santiago , Chile.,c Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile , Santiago , Chile.,d Faculty of Health Sciences , Universidad Central de Chile , Santiago , Chile
| | - Vicente A Torres
- a Institute for Research in Dental Sciences, Faculty of Dentistry , Universidad de Chile , Santiago , Chile.,c Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile , Santiago , Chile.,d Faculty of Health Sciences , Universidad Central de Chile , Santiago , Chile
| |
Collapse
|
|
42
|
Saarinen L, Nummela P, Leinonen H, Heiskanen A, Thiel A, Haglund C, Lepistö A, Satomaa T, Hautaniemi S, Ristimäki A. Glycomic Profiling Highlights Increased Fucosylation in Pseudomyxoma Peritonei. Mol Cell Proteomics 2018; 17:2107-2118. [PMID: 30072579 DOI: 10.1074/mcp.ra118.000615] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 07/31/2018] [Indexed: 12/23/2022] Open
Abstract
Pseudomyxoma peritonei (PMP) is a subtype of mucinous adenocarcinoma that most often originates from the appendix, and grows in the peritoneal cavity filling it with mucinous ascites. KRAS and GNAS mutations are frequently found in PMP, but other common driver mutations are infrequent. As altered glycosylation can promote carcinogenesis, we compared N-linked glycan profiles of PMP tissues to those of normal appendix. Glycan profiles of eight normal appendix samples and eight low-grade and eight high-grade PMP specimens were analyzed by mass spectrometry. Our results show differences in glycan profiles between PMP and the controls, especially in those of neutral glycans, and the most prominent alteration was increased fucosylation. We further demonstrate up-regulated mRNA expression of four fucosylation-related enzymes, the core fucosylation performing fucosyltransferase 8 and three GDP-fucose biosynthetic enzymes in PMP tissues when compared with the controls. Up-regulated protein expression of the latter three enzymes was further observed in PMP cells by immunohistochemistry. We also demonstrate that restoration of fucosylation either by salvage pathway or by introduction of an expression of intact GDP-mannose 4,6-dehydratase enhance expression of MUC2, which is the predominant mucin molecule secreted by the PMP cells, in an intestinal-derived adenocarcinoma cell line with defective fucosylation because of deletion in the GDP-mannose 4,6-dehydratase gene. Thus, altered glycosylation especially in the form of fucosylation is linked to the characteristic mucin production of PMP. Glycomic data are available via ProteomeXchange with identifier PXD010086.
Collapse
Affiliation(s)
- Lilli Saarinen
- From the ‡Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, P.O. Box 63, FI-00014 University of Helsinki, Finland
| | - Pirjo Nummela
- From the ‡Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, P.O. Box 63, FI-00014 University of Helsinki, Finland
| | - Hannele Leinonen
- From the ‡Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, P.O. Box 63, FI-00014 University of Helsinki, Finland
| | | | - Alexandra Thiel
- From the ‡Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, P.O. Box 63, FI-00014 University of Helsinki, Finland
| | - Caj Haglund
- ¶Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 440, FI-00029 HUS, Finland.,‖Translational Cancer Biology, Research Programs Unit, University of Helsinki, P.O. Box 63, FI-00014 University of Helsinki, Finland
| | - Anna Lepistö
- ¶Department of Surgery, University of Helsinki and Helsinki University Hospital, P.O. Box 440, FI-00029 HUS, Finland
| | - Tero Satomaa
- §Glykos Finland Ltd, Viikinkaari 6, FI-00790 Helsinki, Finland
| | - Sampsa Hautaniemi
- From the ‡Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, P.O. Box 63, FI-00014 University of Helsinki, Finland
| | - Ari Ristimäki
- From the ‡Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, P.O. Box 63, FI-00014 University of Helsinki, Finland; .,**Department of Pathology, HUSLAB, University of Helsinki and Helsinki University Hospital, P.O. Box 400, FI-00029 HUS, Finland
| |
Collapse
|
|
43
|
Guo D, Guo J, Li X, Guan F. Enhanced motility and proliferation by miR-10b/FUT8/p-AKT axis in breast cancer cells. Oncol Lett 2018; 16:2097-2104. [PMID: 30008906 PMCID: PMC6036446 DOI: 10.3892/ol.2018.8891] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 11/07/2017] [Indexed: 12/30/2022] Open
Abstract
Upregulation of microRNA (miR)-10b has been confirmed in multiple types of cancer, however, the role of miR-10b in glycosylation remains unclear. Protein core-fucosylation is an important N-linked glycosylation modification and serves important roles in cancer progression. In a previous study, a glycogene array was applied to profile the alterations of glycogene expression in miR-10b-overexpressed MCF10A cells. Notably, fucosyltranferase 8 (FUT8), which is responsible for the addition of core-fucose to N-glycan, was significantly upregulated by miR-10b. In the present study, increased motility and proliferation were observed in miR-10b-overexpressed MCF10A cells. To assess the mechanism involved, the role of FUT8 in MCF10A cells was studied and it was confirmed that miR-10b promotes motility and proliferation by regulating FUT8 and activating the protein kinase B (AKT) signaling pathway. Consistent with the aforementioned result, decreased motility and proliferation were detected when miR-10b expression was inhibited in MDA-MB-231 cells, transforming growth factor-β-induced and Twist-overexpressed MCF10A cells. To conclude, the findings from the present study indicate that miR-10b promotes motility and proliferation by increasing FUT8 and activating AKT in breast cancer cells.
Collapse
Affiliation(s)
- Dong Guo
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Jia Guo
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Xiang Li
- Wuxi Medical School, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| | - Feng Guan
- Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 214122, P.R. China
| |
Collapse
|
|
44
|
Okada M, Chikuma S, Kondo T, Hibino S, Machiyama H, Yokosuka T, Nakano M, Yoshimura A. Blockage of Core Fucosylation Reduces Cell-Surface Expression of PD-1 and Promotes Anti-tumor Immune Responses of T Cells. Cell Rep 2018; 20:1017-1028. [PMID: 28768188 DOI: 10.1016/j.celrep.2017.07.027] [Citation(s) in RCA: 173] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 06/15/2017] [Accepted: 07/12/2017] [Indexed: 12/23/2022] Open
Abstract
Programmed cell death 1 (PD-1) is highly expressed on exhausted T cells and inhibits T cell activation. Antibodies that block the interaction between PD-1 and its ligand prevent this inhibitory signal and reverse T cell dysfunction, providing beneficial anti-tumor responses in a substantial number of patients. Mechanisms for the induction and maintenance of high PD-1 expression on exhausted T cells have not been fully understood. Utilizing a genome-wide loss-of-function screening method based on the CRISPR-Cas9 system, we identified genes involved in the core fucosylation pathway as positive regulators of cell-surface PD-1 expression. Inhibition of Fut8, a core fucosyltransferase, by genetic ablation or pharmacologic inhibition reduced cell-surface expression of PD-1 and enhanced T cell activation, leading to more efficient tumor eradication. Taken together, our findings suggest that blocking core fucosylation of PD-1 can be a promising strategy for improving anti-tumor immune responses.
Collapse
Affiliation(s)
- Masahiro Okada
- Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
| | - Shunsuke Chikuma
- Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Taisuke Kondo
- Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Sana Hibino
- Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Hiroaki Machiyama
- Department of Immunology, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Tadashi Yokosuka
- Department of Immunology, Tokyo Medical University, Shinjuku-ku, Tokyo 160-8402, Japan
| | - Miyako Nakano
- Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-hiroshima, Hiroshima 739-8530, Japan
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
| |
Collapse
|
|
45
|
Höti N, Yang S, Hu Y, Shah P, Haffner MC, Zhang H. Overexpression of α (1,6) fucosyltransferase in the development of castration-resistant prostate cancer cells. Prostate Cancer Prostatic Dis 2018; 21:137-146. [PMID: 29339807 PMCID: PMC5895601 DOI: 10.1038/s41391-017-0016-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 09/14/2017] [Indexed: 01/07/2023]
Abstract
Glycosylation is recognized as one of the most common modifications on proteins. Recent studies have shown that aberrant expression of α (1,6) fucosyltransferase (FUT8), which catalyzes the transfer of fucose from GDP-fucose to core-GlcNAc of the N-linked glycoproteins, modulates cellular behavior that could lead to the development of aggressive prostate cancer. While the relationship between the abnormal expression of FUT8 and glycoprotein fucosylation in different prostate cancer cells has been demonstrated, there is no evidence that shows dysregulated fucosylation might be involved in prostate cancer progression from androgen-dependent to castration-resistant prostate cancer. In this study, using a proteomics approach, we analyzed androgen-dependent and androgen-resistant LAPC4 cells and identified FUT8 to be significantly overexpressed in the androgen-resistant LAPC4 cells. These findings were independently confirmed in LAPC4 cells that were treated with non-steroidal anti-androgen (bicalutamide) and in the in vivo castrated tumor xenograft models. Similarly, we also demonstrated that overexpression of FUT8 might be responsible for the decreased PSA expression in prostate cancer specimens. To our knowledge, this is the first study reporting the functional role of fucosylated enzyme in the development of castration-resistant prostate cancer.
Collapse
Affiliation(s)
- Naseruddin Höti
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Shuang Yang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Yingwei Hu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Punit Shah
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Michael C Haffner
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Hui Zhang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
| |
Collapse
|
|
46
|
Möginger U, Grunewald S, Hennig R, Kuo CW, Schirmeister F, Voth H, Rapp E, Khoo KH, Seeberger PH, Simon JC, Kolarich D. Alterations of the Human Skin N- and O-Glycome in Basal Cell Carcinoma and Squamous Cell Carcinoma. Front Oncol 2018; 8:70. [PMID: 29619343 PMCID: PMC5871710 DOI: 10.3389/fonc.2018.00070] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 03/01/2018] [Indexed: 12/20/2022] Open
Abstract
The glycome of one of the largest and most exposed human organs, the skin, as well as glycan changes associated with non-melanoma skin cancers have not been studied in detail to date. Skin cancers such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are among the most frequent types of cancers with rising incidence rates in the aging population. We investigated the healthy human skin N- and O-glycome and its changes associated with BCC and SCC. Matched patient samples were obtained from frozen biopsy and formalin-fixed paraffin-embedded tissue samples for glycomics analyses using two complementary glycomics approaches: porous graphitized carbon nano-liquid chromatography electro spray ionization tandem mass spectrometry and capillary gel electrophoresis with laser induced fluorescence detection. The human skin N-glycome is dominated by complex type N-glycans that exhibit almost similar levels of α2-3 and α2-6 sialylation. Fucose is attached exclusively to the N-glycan core. Core 1 and core 2 type O-glycans carried up to three sialic acid residues. An increase of oligomannose type N-glycans and core 2 type O-glycans was observed in BCC and SCC, while α2-3 sialylation levels were decreased in SCC but not in BCC. Furthermore, glycopeptide analyses provided insights into the glycoprotein candidates possibly associated with the observed N-glycan changes, with glycoproteins associated with binding events being the most frequently identified class.
Collapse
Affiliation(s)
- Uwe Möginger
- Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.,Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Sonja Grunewald
- Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany
| | - René Hennig
- Department of Bioprocess Engineering, Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.,glyXera GmbH, Magdeburg, Germany
| | - Chu-Wei Kuo
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Falko Schirmeister
- Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.,Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Harald Voth
- Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany
| | - Erdmann Rapp
- Department of Bioprocess Engineering, Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.,glyXera GmbH, Magdeburg, Germany
| | - Kay-Hooi Khoo
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Peter H Seeberger
- Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.,Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Jan C Simon
- Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany
| | - Daniel Kolarich
- Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.,Institute for Glycomics, Griffith University, Southport, QLD, Australia
| |
Collapse
|
|
47
|
de Freitas Junior JCM, Morgado-Díaz JA. The role of N-glycans in colorectal cancer progression: potential biomarkers and therapeutic applications. Oncotarget 2017; 7:19395-413. [PMID: 26539643 PMCID: PMC4991391 DOI: 10.18632/oncotarget.6283] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 10/22/2015] [Indexed: 12/12/2022] Open
Abstract
Changes in glycosylation, which is one of the most common protein post-translational modifications, are considered to be a hallmark of cancer. N-glycans can modulate cell migration, cell-cell adhesion, cell signaling, growth and metastasis. The colorectal cancer (CRC) is a leading cause of cancer-related mortality and the correlation between CRC progression and changes in the pattern of expression of N-glycans is being considered in the search for new biomarkers. Here, we review the role of N-glycans in CRC cell biology. The perspectives on emerging N-glycan-related anticancer therapies, along with new insights and challenges, are also discussed.
Collapse
Affiliation(s)
| | - José Andrés Morgado-Díaz
- Cellular Biology Program, Structural Biology Group, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| |
Collapse
|
|
48
|
Iijima J, Kobayashi S, Kitazume S, Kizuka Y, Fujinawa R, Korekane H, Shibata T, Saitoh SI, Akashi-Takamura S, Miyake K, Miyoshi E, Taniguchi N. Core fucose is critical for CD14-dependent Toll-like receptor 4 signaling. Glycobiology 2017; 27:1006-1015. [PMID: 28973141 DOI: 10.1093/glycob/cwx075] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 08/21/2017] [Indexed: 02/09/2025] Open
Abstract
Core fucosylation, a posttranslational modification of N-glycans, modifies several growth factor receptors and impacts on their ligand binding affinity. Core-fucose-deficient mice generated by ablating the α1,6 fucosyltransferase enzyme, Fut8, exhibit severe pulmonary emphysema, partly due to impaired macrophage function, similar to aged Toll-like receptor 4 (Tlr4)-deficient mice. We therefore suspect that a lack of core fucose affects the TLR4-dependent signaling pathway. Indeed, upon lipopolysaccharide stimulation, Fut8-deficient mouse embryonic fibroblasts (MEFs) produced similar levels of interleukin-6 but markedly reduced levels of interferon-β (IFN-β) compared with wild-type MEFs. Lectin blot analysis of the TLR4 signaling complex revealed that core fucosylation was specifically found on CD14. Even though similar levels of TLR4/myeloid differentiation factor 2 (MD2) activation and dimerization were observed in Fut8-deficient cells after lipopolysaccharide stimulation, internalization of TLR4 and CD14 was significantly impaired. Given that internalized TLR4/MD2 induces IFN-β production, impaired IFN-β production in Fut8-deficient cells is ascribed to impaired TLR4/MD2 internalization. These data show for the first time that glycosylation critically regulates TLR4 signaling.
Collapse
Affiliation(s)
- Junko Iijima
- Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Satoshi Kobayashi
- Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Shinobu Kitazume
- Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Yasuhiko Kizuka
- Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Reiko Fujinawa
- Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Hiroaki Korekane
- Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Takuma Shibata
- Division of Innate Immunity, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Shin-Ichiroh Saitoh
- Division of Innate Immunity, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Sachiko Akashi-Takamura
- Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Aichi 480-1195, Japan
| | - Kensuke Miyake
- Division of Innate Immunity, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Naoyuki Taniguchi
- Disease Glycomics Team, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| |
Collapse
|
|
49
|
Kizuka Y, Nakano M, Yamaguchi Y, Nakajima K, Oka R, Sato K, Ren CT, Hsu TL, Wong CH, Taniguchi N. An Alkynyl-Fucose Halts Hepatoma Cell Migration and Invasion by Inhibiting GDP-Fucose-Synthesizing Enzyme FX, TSTA3. Cell Chem Biol 2017; 24:1467-1478.e5. [PMID: 29033318 DOI: 10.1016/j.chembiol.2017.08.023] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 07/30/2017] [Accepted: 08/30/2017] [Indexed: 12/30/2022]
Abstract
Fucosylation is a glycan modification critically involved in cancer and inflammation. Although potent fucosylation inhibitors are useful for basic and clinical research, only a few inhibitors have been developed. Here, we focus on a fucose analog with an alkyne group, 6-alkynyl-fucose (6-Alk-Fuc), which is used widely as a detection probe for fucosylated glycans, but is also suggested for use as a fucosylation inhibitor. Our glycan analysis using lectin and mass spectrometry demonstrated that 6-Alk-Fuc is a potent and general inhibitor of cellular fucosylation, with much higher potency than the existing inhibitor, 2-fluoro-fucose (2-F-Fuc). The action mechanism was shown to deplete cellular GDP-Fuc, and the direct target of 6-Alk-Fuc is FX (encoded by TSTA3), the bifunctional GDP-Fuc synthase. We also show that 6-Alk-Fuc halts hepatoma invasion. These results highlight the unappreciated role of 6-Alk-Fuc as a fucosylation inhibitor and its potential use for basic and clinical science.
Collapse
Affiliation(s)
- Yasuhiko Kizuka
- Disease Glycomics Team, Global Research Cluster, RIKEN, Wako, Saitama 351-0198, Japan
| | - Miyako Nakano
- Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashihiroshima, Hiroshima 739-8530, Japan
| | - Yoshiki Yamaguchi
- Structural Glycobiology Team, Global Research Cluster, RIKEN, Wako, Saitama 351-0198, Japan
| | - Kazuki Nakajima
- Division of Clinical Research Promotion and Support, Center for Research Promotion, Fujita Health University, Toyoake, Aichi 470-1192, Japan
| | - Ritsuko Oka
- Disease Glycomics Team, Global Research Cluster, RIKEN, Wako, Saitama 351-0198, Japan
| | - Keiko Sato
- Disease Glycomics Team, Global Research Cluster, RIKEN, Wako, Saitama 351-0198, Japan
| | - Chien-Tai Ren
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
| | - Tsui-Ling Hsu
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
| | - Chi-Huey Wong
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
| | - Naoyuki Taniguchi
- Disease Glycomics Team, Global Research Cluster, RIKEN, Wako, Saitama 351-0198, Japan.
| |
Collapse
|
|
50
|
Hsiao CT, Cheng HW, Huang CM, Li HR, Ou MH, Huang JR, Khoo KH, Yu HW, Chen YQ, Wang YK, Chiou A, Kuo JC. Fibronectin in cell adhesion and migration via N-glycosylation. Oncotarget 2017; 8:70653-70668. [PMID: 29050309 PMCID: PMC5642584 DOI: 10.18632/oncotarget.19969] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 07/18/2017] [Indexed: 02/07/2023] Open
Abstract
Directed cell migration is an important step in effective wound healing and requires the dynamic control of the formation of cell-extracellular matrix interactions. Plasma fibronectin is an extracellular matrix glycoprotein present in blood plasma that plays crucial roles in modulating cellular adhesion and migration and thereby helping to mediate all steps of wound healing. In order to seek safe sources of plasma fibronectin for its practical use in wound dressing, we isolated fibronectin from human (homo) and porcine plasma and demonstrated that both have a similar ability as a suitable substrate for the stimulation of cell adhesion and for directing cell migration. In addition, we also defined the N-glycosylation sites and N-glycans present on homo and porcine plasma fibronectin. These N-glycosylation modifications of the plasma fibronectin synergistically support the integrin-mediated signals to bring about mediating cellular adhesion and directed cell migration. This study not only determines the important function of N-glycans in both homo and porcine plasma fibronectin-mediated cell adhesion and directed cell migration, but also reveals the potential applications of porcine plasma fibronectin if it was applied as a material for clinical wound healing and tissue repair.
Collapse
Affiliation(s)
- Cheng-Te Hsiao
- Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan.,Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan
| | - Hung-Wei Cheng
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan
| | - Chi-Ming Huang
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan
| | - Hao-Ru Li
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan
| | - Meng-Hsin Ou
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan
| | - Jie-Rong Huang
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan
| | - Kay-Hooi Khoo
- Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan.,Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan
| | - Helen Wenshin Yu
- Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei 11221, Taiwan
| | - Yin-Quan Chen
- Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei 11221, Taiwan
| | - Yang-Kao Wang
- Department of Cell Biology and Anatomy, National Cheng Kung University, Tainan 70101, Taiwan
| | - Arthur Chiou
- Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei 11221, Taiwan.,Institute of Biophotonics, National Yang-Ming University, Taipei 11221, Taiwan
| | - Jean-Cheng Kuo
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.,Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei 11221, Taiwan.,Proteomics Research Center, National Yang-Ming University, Taipei 11221, Taiwan
| |
Collapse
|