Dublin-Oxford NIBRT Glycobiology Laboratory, NIBRT, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
Epigenetics. 2011 Nov;6(11):1362-72. doi: 10.4161/epi.6.11.17977. Epub 2011 Nov 1.
Glycosylation is the most common posttranslational modification of proteins and is highly reflective of changes in the environment of a cell. Epigenetic modifications to the genome are stably transmitted to daughter cells without the requirement for genetic sequence alterations. Aberrant regulation of both epigenetic programming and glycosylation patterning are integral aspects of carcinogenesis. The objective of this study was to determine the interplay between these two complex cellular processes. We demonstrate that global DNA methylation changes in ovarian cancer epithelial cells (OVCAR3) resulted in significant alterations in the glycosylation of secreted glycoproteins. These changes included a reduction in core fucosylation, increased branching and increased sialylation. We further show that the change in core fucose levels was mirrored by altered expression of GMDS and FX, key enzymes in fucose biosynthesis. Alterations in the expression of key glycosyltransferase enzymes such as MGAT5 reflect the changes seen in the branching and sialylation of secreted glycans. Overall, our results highlight that modifications to the epigenetic machinery have a profound effect on the glycan structures generated by cells, which may be a key step in understanding metastasis and drug resistance during cancer progression.
糖基化是蛋白质最常见的翻译后修饰，高度反映了细胞环境的变化。基因组的表观遗传修饰可以稳定地传递给子细胞，而不需要遗传序列的改变。异常的表观遗传编程和糖基化模式调节是癌变的重要方面。本研究的目的是确定这两个复杂细胞过程之间的相互作用。我们证明，卵巢癌细胞（OVCAR3）中的全基因组 DNA 甲基化变化导致分泌糖蛋白的糖基化发生显著改变。这些变化包括核心岩藻糖基化减少、分支增加和唾液酸化增加。我们进一步表明，核心岩藻糖水平的变化反映了在岩藻糖生物合成中关键酶 GMDS 和 FX 的表达改变。关键糖基转移酶酶如 MGAT5 的表达改变反映了分泌聚糖分支和唾液酸化的变化。总的来说，我们的结果强调了表观遗传机制的改变对细胞产生的聚糖结构有深远的影响，这可能是理解癌症进展过程中转移和耐药性的关键步骤。
