Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients
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Authors
Kohler, Reto
Anugraham, Merrina
Nunez Lopez, Monica
Xiao, Christina
Schoetzau, Andreas
Fedier, André
Jacob, Francis
Heinzelmann-Schwarz, Viola
Author (Corporation)
Publication date
12.07.2016
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Type
01A - Journal article
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Parent work
Oncotarget
Special issue
DOI of the original publication
Series
Series number
Volume
7
Issue / Number
32
Pages / Duration
51674
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Publisher / Publishing institution
Impact Journals LLC
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Abstract
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
Keywords
dna methylation, n-glycosylation, bisecting glcnac, long-time survival, ovarian cancer
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ISBN
ISSN
1949-2553
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
Review
Peer review of the complete publication
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License
Citation
Kohler, R., Anugraham, M., Nunez Lopez, M., Xiao, C., Schoetzau, A., Hettich, T., Schlotterbeck, G., Fedier, A., Jacob, F., & Heinzelmann-Schwarz, V. (2016). Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients. Oncotarget, 7(32), 51674. https://doi.org/10.18632/oncotarget.10543