title: Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients.
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 GlcNAc and demonstrate the importance of N-glycosylation in cancer progression.
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Reto S
authors.initials: RS
authors.lastname: Kohler
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Merrina
authors.initials: M
authors.lastname: Anugraham
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Mónica Núñez
authors.initials: MN
authors.lastname: López
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Christina
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schoetzau
authors.affiliation: School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Hettich
authors.affiliation: School of Life Sciences, University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland.
authors.forename: Goetz
authors.initials: G
authors.lastname: Schlotterbeck
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: André
authors.initials: A
authors.lastname: Fedier
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.|Glyco-Oncology, Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.
authors.forename: Francis
authors.initials: F
authors.lastname: Jacob
authors.affiliation: Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.|Hospital for Women, Department of Gynecology and Gynecological Oncology, University Hospital Basel, Basel, Switzerland.
authors.forename: Viola
authors.initials: V
authors.lastname: Heinzelmann-Schwarz
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002240:Carbohydrate Sequence; D000077216:Carcinoma, Ovarian Epithelial; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D011134:Polysaccharides; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase; D000117:Acetylglucosamine
keywords: DNA methylation; N-glycosylation; bisecting GlcNAc; long-time survival; ovarian cancer