Home LiteratureArticle Details
PMID: 32599982 Published · ppublish English Journal Article

β1,4-Galactosyltransferase V Modulates Breast Cancer Stem Cells through Wnt/β-catenin Signaling Pathway.

Cancer research and treatment ·Vol. 52 ·No. 4 ·2020-10-00 ·Pages 1084-1102

Tang W, Li M, Qi X, Li J

Abstract

Breast cancer stem cells (BCSCs) contribute to the initiation, development, and recurrence of breast carcinomas. β1,4-Galactosyltransferase V (B4GalT5), which catalyzes the addition of galactose to GlcNAcβ1-4Man of N-glycans, is involved in embryogenesis. However, its role in the modulation of BCSCs remains unknown. The relationship between B4GalT5 and breast cancer stemness was investigated by online clinical databases and immunohistochemistry analysis. Mammosphere formation, fluorescence-activated cell sorting (FACS), and in-vivo assays were used to evaluate B4GalT5 expression in BCSCs and its effect on BCSCs. B4GalT5 regulation of Wnt/β-catenin signaling was examined by immunofluorescence and Ricinus communis agglutinin I pull-down assays. Cell surface biotinylation and FACS assays were performed to assess the association of cell surface B4GalT5 and BCSCs. B4GalT5, but not other B4GalTs, was highly correlated with BCSC markers and poor prognosis. B4GalT5 significantly increased the stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) and promoted the production of CD44+CD24-/low cells and the formation of mammospheres. Furthermore, B4GalT5 overexpression resulted in dramatic tumor growth in vivo. Mechanistically, B4GalT5 modified and protected Frizzled-1 from degradation via the lysosomal pathway, promoting Wnt/β-catenin signaling which was hyperactivated in BCSCs. B4GalT5, located on the surface of a small subset of breast carcinoma cells, was not responsible for the stemness of BCSCs. B4GalT5 modulates the stemness of breast cancer through glycosylation modification to stabilize Frizzled-1 and activate Wnt/β-catenin signaling independent of its cell surface location. Our studies highlight a previously unknown role of B4GalT5 in regulating the stemness of breast cancer and provide a potential drug target for anticancer drug development.

Keywords
4-Galactosyltransferase V Breast cancer stem cell Cellular location Frizzled-1 Glycosylation β1
MeSH Terms
Aldehyde Dehydrogenase 1 Family/analysis,metabolism Animals Breast/pathology Breast Neoplasms/pathology Carcinoma, Ductal, Breast/pathology Cell Line, Tumor Cell Proliferation Datasets as Topic Female Frizzled Receptors/metabolism Galactosyltransferases/genetics,metabolism Gene Knockdown Techniques Humans Mice Neoplastic Stem Cells/pathology Proteolysis Retinal Dehydrogenase/analysis,metabolism Tissue Array Analysis Wnt Signaling Pathway Xenograft Model Antitumor Assays
Chemicals
FZD1 protein, human Frizzled Receptors Aldehyde Dehydrogenase 1 Family ALDH1A1 protein, human Retinal Dehydrogenase B4GALT5 protein, human Galactosyltransferases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Tang Wei
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
Li Meng
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
Qi Xin
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
Li Jing
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China. | Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, China. | Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China.
References (28)
28 references, click to expand
  1. Therapeutics strategies against cancer stem cell in breast cancer.
    Int J Biochem Cell Biol. 2019 Apr;109:76-81 PMID: 30772480
  2. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses.
    Nucleic Acids Res. 2017 Jul 3;45(W1):W98-W102 PMID: 28407145
  3. MYC Inhibition Depletes Cancer Stem-like Cells in Triple-Negative Breast Cancer.
    Cancer Res. 2017 Dec 1;77(23):6641-6650 PMID: 28951456
  4. Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review).
    Int J Oncol. 2017 Nov;51(5):1357-1369 PMID: 29048660
  5. Lactosylceramide synthases encoded by B4galt5 and 6 genes are pivotal for neuronal generation and myelin formation in mice.
    PLoS Genet. 2018 Aug 16;14(8):e1007545 PMID: 30114188
  6. Distinct roles of N-glycosylation at different sites of corin in cell membrane targeting and ectodomain shedding.
    J Biol Chem. 2015 Jan 16;290(3):1654-63 PMID: 25451932
  7. Protein arginine methyltransferase 5 (PRMT5) promotes survival of lymphoma cells via activation of WNT/β-catenin and AKT/GSK3β proliferative signaling.
    J Biol Chem. 2019 May 10;294(19):7692-7710 PMID: 30885941
  8. Identification of key functional residues in the active site of human {beta}1,4-galactosyltransferase 7: a major enzyme in the glycosaminoglycan synthesis pathway.
    J Biol Chem. 2010 Nov 26;285(48):37342-58 PMID: 20843813
  9. Effects of glycosylation on the stability of protein pharmaceuticals.
    J Pharm Sci. 2009 Apr;98(4):1223-45 PMID: 18661536
  10. Tumor beta-1,4-galactosyltransferase IV overexpression is closely associated with colorectal cancer metastasis and poor prognosis.
    Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8615-22 PMID: 16361545
  11. Glycosylation in cancer: mechanisms and clinical implications.
    Nat Rev Cancer. 2015 Sep;15(9):540-55 PMID: 26289314
  12. The relationship between early embryo development and tumourigenesis.
    J Cell Mol Med. 2010 Dec;14(12):2697-701 PMID: 21029369
  13. Targeted mutations in beta1,4-galactosyltransferase I reveal its multiple cellular functions.
    Biochim Biophys Acta. 2002 Dec 19;1573(3):258-70 PMID: 12417408
  14. Cancer stem cells: current status and evolving complexities.
    Cell Stem Cell. 2012 Jun 14;10(6):717-728 PMID: 22704512
  15. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
    CA Cancer J Clin. 2018 Nov;68(6):394-424 PMID: 30207593
  16. Stemness marker ALDH1A1 promotes tumor angiogenesis via retinoic acid/HIF-1α/VEGF signalling in MCF-7 breast cancer cells.
    J Exp Clin Cancer Res. 2018 Dec 12;37(1):311 PMID: 30541574
  17. N-Glycosylation at Asn 402 Stabilizes N-Cadherin and Promotes Cell-Cell Adhesion of Glioma Cells.
    J Cell Biochem. 2017 Jun;118(6):1423-1431 PMID: 27864899
  18. Localization of the long form of beta-1,4-galactosyltransferase to the plasma membrane and Golgi complex of 3T3 and F9 cells by immunofluorescence confocal microscopy.
    Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10913-7 PMID: 7971983
  19. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients.
    Breast Cancer Res Treat. 2010 Oct;123(3):725-31 PMID: 20020197
  20. WNT-3A regulates an Axin1/NRF2 complex that regulates antioxidant metabolism in hepatocytes.
    Antioxid Redox Signal. 2015 Mar 1;22(7):555-71 PMID: 25336178
  21. Wnt Signaling Promotes Breast Cancer by Blocking ITCH-Mediated Degradation of YAP/TAZ Transcriptional Coactivator WBP2.
    Cancer Res. 2016 Nov 1;76(21):6278-6289 PMID: 27578003
  22. Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity.
    Nat Commun. 2016 Aug 30;7:12632 PMID: 27572267
  23. Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors.
    J Cell Biol. 2011 Feb 21;192(4):557-67 PMID: 21321100
  24. Involvement of chemokine receptors in breast cancer metastasis.
    Nature. 2001 Mar 1;410(6824):50-6 PMID: 11242036
  25. Revisiting the role of ABC transporters in multidrug-resistant cancer.
    Nat Rev Cancer. 2018 Jul;18(7):452-464 PMID: 29643473
  26. Inhibition of KLF4 by Statins Reverses Adriamycin-Induced Metastasis and Cancer Stemness in Osteosarcoma Cells.
    Stem Cell Reports. 2017 Jun 6;8(6):1617-1629 PMID: 28552603
  27. The sweet and sour of cancer: glycans as novel therapeutic targets.
    Nat Rev Cancer. 2005 Jul;5(7):526-42 PMID: 16069816
  28. beta4GalT-II is a key regulator of glycosylation of the proteins involved in neuronal development.
    Biochem Biophys Res Commun. 2005 Jul 22;333(1):131-7 PMID: 15939404
Full Text / Full Text
PMC full text available locally, click to read

Loading full text...

Article Info
Journal
Cancer research and treatment
Abbr.
Cancer Res Treat
ISSN
2005-9256
DOI
10.4143/crt.2020.093
Published
2020-10-00
Epub
2020-00-27
Pages
1084-1102
Language
English
Region
Korea (South)
NLM ID
101155137
PMCID
PMC7577798
Subset
IM
Grants
National Natural Science Foundation of China · 81673450
NSFC Shandong Joint Fund · U1606403
Qingdao National Laboratory for Marine Science and Technology · 2015ASKJ02
Fundamental Research Funds for the Central Universities · 201762002
National Science and Technology Major Project for Significant New Drugs Development · 2018ZX09735-004
External Links
PubMed source DOI: 10.4143/crt.2020.093 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2