Low MGAT3 expression identifies long-term survivors with high grade serous ovarian cancer

• Published in: Geburtshilfe und Frauenheilkunde Vol. 76; no. 10
• Main Authors: Kohler, R, Anugraham, M, Nunez Lopez, M, Xiao, C, Schötzau, A, Hettich, T, Schlotterbeck, G, Fedier, A, Heinzelmann-Schwarz, V, Jacob, F
• Format: Conference Proceeding Journal Article
• Language: English; German
• Published: 13.10.2016
• ISSN: 0016-5751; 1438-8804
• DOI: 10.1055/s-0036-1593243

Introduction: MGAT3 gene expression is implicated in oncogenic signaling pathways. We recently found that MGAT3 expression correlated with the presence of bisecting GlcNAc on N-glycoproteins in ovarian cancer cells. MGAT3 encodes the enzyme attaching bisecting GlcNAc to these glycoproteins. We investigated (i) how MGAT3 expression is regulated, (ii) whether DNA methylation, MGAT3 expression, and bisecting GlcNAc presence are functionally linked, and (iii) whether MGAT3 expression has any predictive value. Material and methods: DNA methylation and MGAT3 expression were analyzed for different cancer types using the TCGA dataset; bisecting GlcNAc detected by mass spectrometry; detailed CpG-island and regulatory genomic region analysis using web-based bioinformatic engines; MGAT3 reconstitution with 5-Aza (DNA methyltransferase-inhibitor) determined by RT-qPCR. Results: TCGA dataset (n = 6118 samples) revealed a longer overall survival in cancer patients with reduced MGAT3 expression. This was particularly dramatic in a subgroup of high-grade serous ovarian cancers, identifying them as long-term survivors. The anticipated key regulatory unit, a genomic region with 37 CpGs at the transcription start site, was hypomethylated in OVCAR3 and A2780 ovarian cancer cells and associated with elevated MGAT3 expression. It was hypermethylated in normal ovarian surface epithelial (HOSE) cells associated with absence of MGAT3. 5-Aza reconstituted MGAT3 expression in HOSE cells, coinciding with reduced DNA methylation, and also in hypermethylated OVCAR8 cells, resulting in bisecting GlcNAc re-expression. Conclusion: Low MGAT3 expression is a predictive marker in all cancers but specifically for long-term survivors of ovarian cancer. Epigenetic silencing of the MGAT3-bisecting GlcNAc axis may offer new therapeutical opportunities.