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Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients

Bisecting GlcNAc on N-glycoproteins is described in E-cadherin-, EGF-, Wnt- and integrin- cancer-associated signaling pathways. However, the mechanisms regulating bisecting GlcNAc expression are not clear. Bisecting GlcNAc is attached to N-glycans through beta 1-4 N-acetylglucosaminyl transferase II...

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Autores principales: Kohler, Reto S., Anugraham, Merrina, López, Mónica Núñez, Xiao, Christina, Schoetzau, Andreas, Hettich, Timm, Schlotterbeck, Goetz, Fedier, André, Jacob, Francis, Heinzelmann-Schwarz, Viola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239506/
https://www.ncbi.nlm.nih.gov/pubmed/27429195
http://dx.doi.org/10.18632/oncotarget.10543
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author Kohler, Reto S.
Anugraham, Merrina
López, Mónica Núñez
Xiao, Christina
Schoetzau, Andreas
Hettich, Timm
Schlotterbeck, Goetz
Fedier, André
Jacob, Francis
Heinzelmann-Schwarz, Viola
author_facet Kohler, Reto S.
Anugraham, Merrina
López, Mónica Núñez
Xiao, Christina
Schoetzau, Andreas
Hettich, Timm
Schlotterbeck, Goetz
Fedier, André
Jacob, Francis
Heinzelmann-Schwarz, Viola
author_sort Kohler, Reto S.
collection PubMed
description Bisecting GlcNAc on N-glycoproteins is described in E-cadherin-, EGF-, Wnt- and integrin- cancer-associated signaling pathways. However, the mechanisms regulating bisecting GlcNAc expression are not clear. Bisecting GlcNAc is attached to N-glycans through beta 1-4 N-acetylglucosaminyl transferase III (MGAT3), which is encoded by two exons flanked by high-density CpG islands. Despite a recently described correlation of MGAT3 and bisecting GlcNAc in ovarian cancer cells, it remains unknown whether DNA methylation is causative for the presence of bisecting GlcNAc. Here, we narrow down the regulatory genomic region and show that reconstitution of MGAT3 expression with 5-Aza coincides with reduced DNA methylation at the MGAT3 transcription start site. The presence of bisecting GlcNAc on released N-glycans was detected by mass spectrometry (LC-ESI-qTOF-MS/MS) in serous ovarian cancer cells upon DNA methyltransferase inhibition. The regulatory impact of DNA methylation on MGAT3 was further evaluated in 18 TCGA cancer types (n = 6118 samples) and the results indicate an improved overall survival in patients with reduced MGAT3 expression, thereby identifying long-term survivors of high-grade serous ovarian cancers (HGSOC). Epigenetic activation of MGAT3 was also confirmed in basal-like breast cancers sharing similar molecular and genetic features with HGSOC. These results provide novel insights into the epigenetic regulation of MGAT3/bisecting GlcNAc and demonstrate the importance of N-glycosylation in cancer progression.
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spelling pubmed-52395062017-01-24 Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients Kohler, Reto S. Anugraham, Merrina López, Mónica Núñez Xiao, Christina Schoetzau, Andreas Hettich, Timm Schlotterbeck, Goetz Fedier, André Jacob, Francis Heinzelmann-Schwarz, Viola Oncotarget Research Paper Bisecting GlcNAc on N-glycoproteins is described in E-cadherin-, EGF-, Wnt- and integrin- cancer-associated signaling pathways. However, the mechanisms regulating bisecting GlcNAc expression are not clear. Bisecting GlcNAc is attached to N-glycans through beta 1-4 N-acetylglucosaminyl transferase III (MGAT3), which is encoded by two exons flanked by high-density CpG islands. Despite a recently described correlation of MGAT3 and bisecting GlcNAc in ovarian cancer cells, it remains unknown whether DNA methylation is causative for the presence of bisecting GlcNAc. Here, we narrow down the regulatory genomic region and show that reconstitution of MGAT3 expression with 5-Aza coincides with reduced DNA methylation at the MGAT3 transcription start site. The presence of bisecting GlcNAc on released N-glycans was detected by mass spectrometry (LC-ESI-qTOF-MS/MS) in serous ovarian cancer cells upon DNA methyltransferase inhibition. The regulatory impact of DNA methylation on MGAT3 was further evaluated in 18 TCGA cancer types (n = 6118 samples) and the results indicate an improved overall survival in patients with reduced MGAT3 expression, thereby identifying long-term survivors of high-grade serous ovarian cancers (HGSOC). Epigenetic activation of MGAT3 was also confirmed in basal-like breast cancers sharing similar molecular and genetic features with HGSOC. These results provide novel insights into the epigenetic regulation of MGAT3/bisecting GlcNAc and demonstrate the importance of N-glycosylation in cancer progression. Impact Journals LLC 2016-07-12 /pmc/articles/PMC5239506/ /pubmed/27429195 http://dx.doi.org/10.18632/oncotarget.10543 Text en Copyright: © 2016 Kohler et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Kohler, Reto S.
Anugraham, Merrina
López, Mónica Núñez
Xiao, Christina
Schoetzau, Andreas
Hettich, Timm
Schlotterbeck, Goetz
Fedier, André
Jacob, Francis
Heinzelmann-Schwarz, Viola
Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients
title Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients
title_full Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients
title_fullStr Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients
title_full_unstemmed Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients
title_short Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients
title_sort epigenetic activation of mgat3 and corresponding bisecting glcnac shortens the survival of cancer patients
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239506/
https://www.ncbi.nlm.nih.gov/pubmed/27429195
http://dx.doi.org/10.18632/oncotarget.10543
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