The β-linked N-acetyl-D-glucosamine (GlcNAc) is a post-translational modification of serine and threonine residues catalyzed by the enzyme O-GlcNAc transferase (OGT). Increased OGT expression is a feature of most human cancers and inhibition of OGT decreases cancer cell proliferation. Anti-proliferative effects are attributed to post-translational modifications of known regulators of cancer cell proliferation, such as MYC, FOXM1 and EZH2. In general, OGT amplifies cell-specific phenotype, for example, OGT overexpression enhances reprogramming efficiency of mouse embryonic fibroblasts into stem cells. Genome-wide screens suggest that certain cancers are particularly dependent on OGT, and understanding these addictions is important when considering OGT as a target for cancer therapy. The O-GlcNAc modification is involved in most cellular processes, which raises concerns of on-target undesirable effects of OGT targeting therapy. Yet, emerging evidence suggest that, much like proteasome inhibitors, specific compounds targeting OGT elicit selective anti-proliferative effects in cancer cells, and can prime malignant cells to other treatments. It is therefore essential to gain mechanistic insights on substrate specificity for OGT, develop reagents to more specifically enrich for O-GlcNAc modified proteins, identify O-GlcNAc 'readers' and develop OGT small molecule inhibitors. Here, we review the relevance of OGT in cancer progression and the potential targeting of this metabolic enzyme as a putative oncogene. Contrasting the functions of any candidate oncogene between normal and cancer cells is rarely done, but only by understanding the normal functions of a given factor, it is possible to understand these functions gone awry. Here we review oncogenic functions of OGT.

中文翻译：

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O-GlcNAc 转移酶 - 辅助因子还是成熟的癌基因？

β-连接的 N-乙酰基-D-葡糖胺 (GlcNAc) 是由酶 O-GlcNAc 转移酶 (OGT) 催化的丝氨酸和苏氨酸残基的翻译后修饰。OGT 表达增加是大多数人类癌症的一个特征，抑制 OGT 会降低癌细胞增殖。抗增殖作用归因于已知癌细胞增殖调节因子的翻译后修饰，例如 MYC、FOXM1 和 EZH2。一般而言，OGT 会放大细胞特异性表型，例如，OGT 过表达可提高小鼠胚胎成纤维细胞重编程为干细胞的效率。全基因组筛选表明某些癌症特别依赖于 OGT，在考虑将 OGT 作为癌症治疗的目标时，了解这些成瘾性非常重要。O-GlcNAc 修饰涉及大多数细胞过程，这引起了人们对 OGT 靶向治疗的靶向不良影响的担忧。然而，新出现的证据表明，与蛋白酶体抑制剂非常相似，靶向 OGT 的特定化合物在癌细胞中引发选择性抗增殖作用，并可以使恶性细胞接受其他治疗。因此，必须获得有关 OGT 底物特异性的机制见解，开发试剂以更具体地富集 O-GlcNAc 修饰蛋白，识别 O-GlcNAc“阅读器”并开发 OGT 小分子抑制剂。在这里，我们回顾了 OGT 在癌症进展中的相关性以及这种代谢酶作为推定癌基因的潜在靶向性。很少在正常细胞和癌细胞之间对比任何候选癌基因的功能，而只能通过了解给定因子的正常功能，可以理解这些功能出错了。在这里，我们回顾了 OGT 的致癌功能。