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Aberrant N-glycosylation in cancer: MGAT5 and β1,6-GlcNAc branched N-glycans as critical regulators of tumor development and progression

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Abstract

Background

Changes in protein glycosylation are widely observed in tumor cells. N-glycan branching through adding β1,6-linked N-acetylglucosamine (β1,6-GlcNAc) to an α1,6-linked mannose, which is catalyzed by the N-acetylglucosaminyltransferase V (MGAT5 or GnT-V), is one of the most frequently observed tumor-associated glycan structure formed. Increased levels of this branching structure play a pro-tumoral role in various ways, for example, through the stabilization of growth factor receptors, the destabilization of intercellular adhesion, or the acquisition of a migratory phenotype.

Conclusion

In this review, we provide an updated and comprehensive summary of the physiological and pathophysiological roles of MGAT5 and β1,6-GlcNAc branched N-glycans, including their regulatory mechanisms. Specific emphasis is given to the role of MGAT5 and β1,6-GlcNAc branched N-glycans in cellular mechanisms that contribute to the development and progression of solid tumors. We also provide insight into possible future clinical implications, such as the use of MGAT5 as a prognostic biomarker.

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Abbreviations

5-AZA-dC:

5-Aza-2′-Deoxycytidine

ACC:

Adrenocortical carcinoma

AJ:

Adherens junctions

AKT:

Protein kinase b

Asn:

Asparagine

BAX:

BCL2-associated X protein

BCL2:

B-cell lymphoma 2

BLCA:

Bladder urothelial carcinoma

BRCA:

Breast invasive carcinoma

CA19-9:

Carbohydrate antigen 19 − 9

CA72-4:

Cancer antigen 72 − 4

CAR:

Chimeric antigen receptors

CEACAM6:

Carcinoembryonic antigen-related cell adhesion molecule 6

CESC:

Cervical squamous cell carcinoma and endocervical adenocarcinoma

CHOL:

Cholangio carcinoma

CMS:

Consensus molecular subtypes

COAD:

Colon adenocarcinoma

CRC:

Colorectal cancer

CRISPR/Cas9:

Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9

DC-SIGN:

Dendritic cell-specific ICAM-3 grabbing non-integrin

DLBC:

Lymphoid neoplasm diffuse large B-cell lymphoma

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial-mesenchymal transition

ER:

Endoplasmic reticulum

ERAD:

Endoplasmic reticulum-associated protein degradation

ESCA:

Esophageal carcinoma

ETS:

Erythroblast transformation-specific transcription factor

FZD-7:

Frizzled class receptor 7

Gal:

Galactose

GATA:

GATA-binding protein

GBM:

Glioblastoma multiforme

GEPIA2:

Gene expression profiling interactive analysis 2

GlcNAc:

N-acetylglucosamine

GPI:

Glycosylphosphatidylinositol

GTEx:

Genotype-tissue expression project

HBP:

Hexosamine biosynthetic pathway

HGF:

Hepatocyte growth factor

HIF1A:

Hypoxia inducible factor 1

HK:

Hexokinase

HNSC:

Head and neck squamous cell carcinoma

IBD:

Inflammatory bowel disease

IFNγ:

Interferon gamma

IGF1:

Insulin-like growth factor 1

IGF-1R:

Insulin-like growth factor 1 receptor

IGF2BP1:

Insulin Like Growth Factor 2 MRNA Binding Protein 1

IgG:

Immunoglobulin G

INSR:

Insulin receptor

KICH:

Kidney chromophobe

KIRC:

Kidney renal clear cell carcinoma

KIRP:

Kidney renal papillary cell carcinoma

LacNAc:

N-acetyl-lactosamine

LAML:

Acute myeloid leukemia

LGG:

Brain lower grade glioma

LIHC:

Liver hepatocelular carcinoma

L-PHA:

Phaseolus vulgaris leucoagglutinin

LUAD:

Lung adenocarcinoma

LUSC:

Lung squamous cell carcinoma

m6a:

N6 methyladenosine

mAbs:

Monoclonal antibodies

Man:

Mannose

MAPK:

Mitogen-activated protein kinase

MESO:

Mesothelioma

MGAT:

N-acetylglucosaminyltransferase

GnT-V:

N-acetylglucosaminyltransferase V

miR-124:

MicroRNA 124

mRNA:

Messenger RNA

MSI:

Microsatellite instability

MT1-MMP:

Membrane-type matrix metalloproteinase-1

MYB:

v-Myb myeloblastosis viral oncogene homolog

mTORC1:

Mammalian target of rapamycin complex 1

ncRNAs:

Non-coding RNAs

NSCLC:

Non-small cell lung cancer

O-GlcNAc:

O-linked β-N-acetylglucosamine

OST:

Oligosaccharyltransferase

OV:

Ovarian serous cystadenocarcinoma

PAAD:

Pancreatic adenocarcinoma

PCPG:

Pheochromocytoma and paraganglioma

PD-1:

Programmed cell death protein-1

PD-L1:

Programmed death ligand-1

PI3K:

Phosphoinositide 3-kinase

PRAD:

Prostate adenocarcinoma

PTEN:

Phosphatase and tensin homolog

PTMs:

Post-translational modifications

RAF:

Cellular homolog of viral raf gene

RAS:

Rat sarcoma viral oncogene homolog

READ:

Rectum adenocarcinoma

RNA:

Ribonucleic acid

SARC:

Sarcoma

SCID:

Severe combined immunodeficiency

Ser:

Serine

siRNA:

Small interfering RNA

SKCM:

Skin cutaneous melanoma

SPPL3:

Signal peptide peptidase like 3

SRC:

v-src avian sarcoma viral oncogene homolog

STAD:

Stomach adenocarcinoma

TCGA:

The cancer genome atlas

TCR:

T-cell receptor

TGCT:

Testicular germ cell tumors

TGF-β1:

Transforming growth factor beta

TGF-βR:

Transforming growth factor beta receptor

THCA:

Thyroid carcinoma

Thr:

Threonine

THYM:

Thymoma

TIM-4:

T-cell immunoglobulin domain and mucin domain 4

TIMP-1:

Tissue inhibitor of metalloproteinase-1

UC:

Ulcerative colitis

UCEC:

Uterine corpus endometrial carcinoma

UCS:

Uterine carcinosarcoma

UDP-GlcNAc:

Uridine diphosphate N-acetylglucosamine

UVM:

Uveal melanoma

WNT:

Wingless-type MMTV integration site family

β1,6-GlcNAc:

β1,6-linked N-acetylglucosamine

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Acknowledgements

Figs. 1, 2, 3, and 6 were created with BioRender.com. The body map and graph of Fig. 4, as well as the survival curves of Fig. 5, were generated with GEPIA2 (gepia2.cancer-pku.cn). We are grateful to all members of the Cellular and Molecular Oncobiology Program, particularly Annie Cristhine Moraes Sousa‑Squiavinato, for assistance and relevant suggestions

Funding

This work was funded by Ministério da Saúde, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).

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  1. Cellular and Molecular Oncobiology Program, Cancer Glycobiology Group, Brazilian National Cancer Institute (INCA), 37 André Cavalcanti Street, Rio de Janeiro, RJ, 20231-050, Brazil

    Michelle de-Souza-Ferreira, Érika Elias Ferreira & Julio Cesar Madureira de-Freitas-Junior

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  1. Michelle de-Souza-Ferreira
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  2. Érika Elias Ferreira
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  3. Julio Cesar Madureira de-Freitas-Junior
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Contributions

Study design: MdSF, EEF, and JCMdFJ. Literature search and data collection: MdSF, EEF, and JCMdFJ. Data analysis: MdSF and JCMdFJ. Manuscript drafting: MdSF, EEF, and JCMdFJ. Manuscript editing and revision: MdSF and JCMdFJ. Supervision: JCMdFJ.

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Correspondence to Julio Cesar Madureira de-Freitas-Junior.

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de-Souza-Ferreira, M., Ferreira, É.E. & de-Freitas-Junior, J.C.M. Aberrant N-glycosylation in cancer: MGAT5 and β1,6-GlcNAc branched N-glycans as critical regulators of tumor development and progression. Cell Oncol. 46, 481–501 (2023). https://doi.org/10.1007/s13402-023-00770-4

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