Chia Joanne, Goh Germaine, Bard Frederic
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 138673, Singapore.
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 138673, Singapore; Department of Biochemistry, National University of Singapore, 21 Lower Kent Ridge, Road, 119077, Singapore.
Biochim Biophys Acta. 2016 Aug;1860(8):1623-39. doi: 10.1016/j.bbagen.2016.03.008. Epub 2016 Mar 8.
While the underlying causes of cancer are genetic modifications, changes in cellular states mediate cancer development. Tumor cells display markedly changed glycosylation states, of which the O-GalNAc glycans called the Tn and TF antigens are particularly common. How these antigens get over-expressed is not clear. The expression levels of glycosylation enzymes fail to explain it.
We describe the regulation of O-GalNAc glycosylation initiation and extension with emphasis on the initiating enzymes ppGalNAcTs (GALNTs), and introduce the GALA pathway--a change in GALNTs compartmentation within the secretory pathway that regulates Tn levels. We discuss the roles of O-GalNAc glycans and GALNTs in tumorigenic processes and finally consider diagnostic and therapeutic perspectives.
Contrary to a common hypothesis, short O-glycans in tumors are not the result of an incomplete glycosylation process but rather reveal the activation of regulatory pathways. Surprisingly, high Tn levels reveal a major shift in the O-glycoproteome rather than a shortening of O-glycans. These changes are driven by membrane trafficking events.
Many attempts to use O-glycans for biomarker, antibody and therapeutic vaccine development have been made, but suffer limitations including poor sensitivity and/or specificity that may in part derive from lack of a mechanistic understanding. Deciphering how short O-GalNAc glycans are regulated would open new perspectives to exploit this biology for therapeutic usage. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.
虽然癌症的根本原因是基因修饰，但细胞状态的变化介导了癌症的发展。肿瘤细胞表现出明显改变的糖基化状态，其中被称为Tn和TF抗原的O-GalNAc聚糖尤为常见。这些抗原如何过度表达尚不清楚。糖基化酶的表达水平无法解释这一现象。
我们描述了O-GalNAc糖基化起始和延伸的调控，重点关注起始酶ppGalNAcTs（GALNTs），并介绍了GALA途径——分泌途径中GALNTs区室化的变化，该变化调节Tn水平。我们讨论了O-GalNAc聚糖和GALNTs在肿瘤发生过程中的作用，最后考虑了诊断和治疗方面的前景。
与普遍假设相反，肿瘤中的短O-聚糖不是糖基化过程不完全的结果，而是揭示了调节途径的激活。令人惊讶的是，高Tn水平揭示了O-糖蛋白组的重大转变，而不是O-聚糖的缩短。这些变化是由膜运输事件驱动的。
许多人尝试将O-聚糖用于生物标志物、抗体和治疗性疫苗的开发，但都存在局限性，包括敏感性和/或特异性较差，这可能部分源于缺乏机制理解。解读短O-GalNAc聚糖是如何被调控的，将为利用这一生物学特性进行治疗开辟新的前景。本文是名为“个性化医学中的聚糖”特刊的一部分，客座编辑：戈尔丹·劳克教授。
