Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, Osaka, Japan.
Department of Molecular Immunology, RIMD, Osaka University, Osaka, Japan.
Mol Aspects Med. 2021 Jun;79:100905. doi: 10.1016/j.mam.2020.100905. Epub 2020 Sep 30.
It is well known that numerous cancer-related changes occur in glycans that are attached to glycoproteins, glycolipids and proteoglycans on the cell surface and these changes in structure and the expression of the glycans are largely regulated by glycosyl-transferases, glycosidases, nucleotide sugars and their related genes. Such structural changes in glycans on cell surface proteins may accelerate the progression, invasion and metastasis of cancer cells. Among the over 200 known glycosyltransferases and related genes, β 1,6 N-acetylglucosaminyltransferase V (GnT-V) (the MGAT5 gene) and α 1,6 fucosyltransferase (FUT8) (the FUT8 gene) are representative enzymes in this respect because changes in glycans caused by these genes appear to be related to cancer metastasis and invasion in vitro as well as in vivo, and a number of reports on these genes in related to epithelial-mesenchymal transition (EMT) have also appeared. Another enzyme, one of the N-glycan branching enzymes, β1,4 N-acetylglucosaminyltransferase III (GnT-III) (the MGAT3 gene) has been reported to suppress EMT. However, there are intermediate states between EMT and mesenchymal-epithelial transition (MET) and some of these genes have been implicated in both EMT and MET and are also probably in an intermediate state. Therefore, it would be difficult to clearly define which specific glycosyltransferase is involved in EMT or MET or an intermediate state. The significance of EMT and N-glycan branching glycosyltransferases needs to be reconsidered and the inhibition of their corresponding genes would also be desirable in therapeutics. This review mainly focuses on GnT-III, GnT-V and FUT8, major players as N-glycan branching enzymes in cancer in relation to EMT programs, and also discusses the catalytic mechanisms of GnT-V and FUT8 whose crystal structures have now been obtained.
众所周知，在细胞表面的糖蛋白、糖脂和蛋白聚糖上连接的聚糖中发生了许多与癌症相关的变化，这些聚糖的结构和表达的变化在很大程度上受到糖基转移酶、糖苷酶、核苷酸糖及其相关基因的调节。细胞表面蛋白上聚糖的这种结构变化可能会加速癌细胞的进展、侵袭和转移。在 200 多种已知的糖基转移酶和相关基因中，β1,6-N-乙酰氨基葡萄糖基转移酶 V（GnT-V）（MGAT5 基因）和α1,6 岩藻糖基转移酶（FUT8）（FUT8 基因）是这方面的代表性酶，因为这些基因引起的糖链变化似乎与体外和体内的癌症转移和侵袭有关，并且也出现了一些关于这些基因与上皮-间充质转化（EMT）相关的报道。另一种酶，一种 N-聚糖分支酶，β1,4-N-乙酰氨基葡萄糖基转移酶 III（GnT-III）（MGAT3 基因）已被报道可抑制 EMT。然而，在 EMT 和间充质上皮转化（MET）之间存在中间状态，其中一些基因已被牵连到 EMT 和 MET 中，并且可能也处于中间状态。因此，很难清楚地定义哪种特定的糖基转移酶参与 EMT 或 MET 或中间状态。需要重新考虑 EMT 和 N-聚糖分支糖基转移酶的意义，并且在治疗中抑制它们相应的基因也是可取的。这篇综述主要集中在 GnT-III、GnT-V 和 FUT8 上，它们是癌症中 N-聚糖分支酶的主要参与者，与 EMT 程序有关，并且还讨论了现在已经获得晶体结构的 GnT-V 和 FUT8 的催化机制。
