Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients
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Reto S. Kohler1, Merrina Anugraham1, Mónica Núñez López1, Christina Xiao1, Andreas Schoetzau1, Timm Hettich2, Goetz Schlotterbeck2, André Fedier1, Francis Jacob1,3,*, Viola Heinzelmann-Schwarz1,4,*
1Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
2School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland
3Glyco-Oncology, Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
4Hospital for Women, Department of Gynecology and Gynecological Oncology, University Hospital Basel, Basel, Switzerland
*These authors contributed equally to this work
Viola Heinzelmann-Schwarz, email: [email protected]
Keywords: N-glycosylation, DNA methylation, long-time survival, bisecting GlcNAc, ovarian cancer
Received: December 18, 2015 Accepted: June 26, 2016 Published: July 12, 2016
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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