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

Kohler, R. S. and Anugraham, M. and Lopez, M. N. and Xiao, C. and Schoetzau, A. and Hettich, T. and Schlotterbeck, G. and Fedier, A. and Jacob, F. and Heinzelmann-Schwarz, V.. (2016) Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients. Oncotarget, 7 (32). pp. 51674-51686.

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Official URL: https://edoc.unibas.ch/61851/

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Gynecological Research (Heinzelmann)
UniBasel Contributors:Heinzelmann, Viola
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1949-2553 (Electronic) 1949-2553 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:31 May 2020 21:26
Deposited On:31 May 2020 21:26

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