Startseite Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3
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Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3

  • Neha M. Sahasrabudhe , Kristiaan Lenos , Joost C. van der Horst , Ernesto Rodríguez und Sandra J. van Vliet ORCID logo EMAIL logo
Veröffentlicht/Copyright: 12. Juni 2018
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 399 Heft 7

Abstract

Colorectal cancer is the third most common cancer type worldwide. It is characterized by a high expression of aberrantly glycosylated ligands, such as the Tn antigen (GalNAcα1-Ser/Thr), which is a major ligand for the C-type lectin macrophage galactose-type lectin (MGL). We have previously determined that a high level of MGL ligands in colorectal tumors is associated with lower disease-free survival in patients with late stage disease, which we could attribute to the presence of oncogenic BRAFV600E mutations. Here we aimed to elucidate the downstream pathway of BRAFV600E governing high MGL ligand and Tn antigen expression. We focused on glycosylation-related enzymes involved in the synthesis or elongation of Tn antigen, N-acetylgalactosamine-transferases (GALNTs) and C1GalT1/COSMC, respectively. Both the activity and expression of C1GalT1 and COSMC were unrelated to the BRAF mutational status. In contrast, GALNT3, GALNT7 and GALNT12 were increased in colorectal cancer cells harboring the BRAFV600E mutation. Through CRISPR-Cas9 gene knockouts we could establish that GALNT3 increased MGL ligand synthesis in the HT29 cell line, while GALNT7 and GALNT12 appeared to have redundant roles. Together our results highlight a novel mechanistic pathway connecting BRAFV600E to aberrant glycosylation in colorectal cancer through GALNT3.

Keywords: C-type lectin; GALNT; glycosylation; Tn antigen

Acknowledgments

This work was supported by a grant from the Cancer Center Amsterdam (CCA2011-5-03, to K.L.), the Dutch Cancer Society (KWF, grant number 6779-VU-2014, to N.S.) and a EU – Horizon 2020 Marie Sklodowska-Curie Grant (No. 642870, ETN-Immunoshape to E.R.).

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Supplemental Material:

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0120).

Received: 2018-01-15
Accepted: 2018-05-12
Published Online: 2018-06-12
Published in Print: 2018-06-27

©2018 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Highlight Issue ‘Molecular Basis of Life 2017’
  3. HIGHLIGHT: GBM Fall Meeting “Molecular Basis of Life 2017”
  4. Neuronal RNP granules: from physiological to pathological assemblies
  5. Regulation of LRRK2: insights from structural and biochemical analysis
  6. The role of (auto)-phosphorylation in the complex activation mechanism of LRRK2
  7. Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3
  8. Hypoxia and serum deprivation induces glycan alterations in triple negative breast cancer cells
  9. Targeting autophagy for the treatment of cancer
  10. From molecules to patients: exploring the therapeutic role of soluble guanylate cyclase stimulators
  11. DNA-encoded libraries – an efficient small molecule discovery technology for the biomedical sciences
  12. Transcytosis of payloads that are non-covalently complexed to bispecific antibodies across the hCMEC/D3 blood-brain barrier model
  13. Mitochondrial contributions to neuronal development and function
  14. Intracellular communication between lipid droplets and peroxisomes: the Janus face of PEX19
  15. Protein crystallization in living cells
  16. Synthetic DNA filaments: from design to applications
  17. Spectroscopic characterization of the Co-substituted C-terminal domain of rubredoxin-2
  18. Twitch or swim: towards the understanding of prokaryotic motion based on the type IV pilus blueprint
https://doi.org/10.1515/hsz-2018-0120
Schlagwörter für diesen Artikel
C-type lectin; GALNT; glycosylation; Tn antigen

Artikel in diesem Heft

  1. Frontmatter
  2. Highlight Issue ‘Molecular Basis of Life 2017’
  3. HIGHLIGHT: GBM Fall Meeting “Molecular Basis of Life 2017”
  4. Neuronal RNP granules: from physiological to pathological assemblies
  5. Regulation of LRRK2: insights from structural and biochemical analysis
  6. The role of (auto)-phosphorylation in the complex activation mechanism of LRRK2
  7. Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3
  8. Hypoxia and serum deprivation induces glycan alterations in triple negative breast cancer cells
  9. Targeting autophagy for the treatment of cancer
  10. From molecules to patients: exploring the therapeutic role of soluble guanylate cyclase stimulators
  11. DNA-encoded libraries – an efficient small molecule discovery technology for the biomedical sciences
  12. Transcytosis of payloads that are non-covalently complexed to bispecific antibodies across the hCMEC/D3 blood-brain barrier model
  13. Mitochondrial contributions to neuronal development and function
  14. Intracellular communication between lipid droplets and peroxisomes: the Janus face of PEX19
  15. Protein crystallization in living cells
  16. Synthetic DNA filaments: from design to applications
  17. Spectroscopic characterization of the Co-substituted C-terminal domain of rubredoxin-2
  18. Twitch or swim: towards the understanding of prokaryotic motion based on the type IV pilus blueprint
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