Sun Lidong, Lv Suli, Song Tanjing
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China.
Discov Oncol. 2021 Nov 24;12(1):54. doi: 10.1007/s12672-021-00450-5.
Prevalent dysregulation of epigenetic modifications plays a pivotal role in cancer. Targeting epigenetic abnormality is a new strategy for cancer therapy. Understanding how conventional oncogenic factors cause epigenetic abnormality is of great basic and translational value. O-GlcNAcylation is a protein modification which affects physiology and pathophysiology. In mammals, O-GlcNAcylation is catalyzed by one single enzyme OGT and removed by one single enzyme OGA. O-GlcNAcylation is affected by the availability of the donor, UDP-GlcNAc, generated by the serial enzymatic reactions in the hexoamine biogenesis pathway (HBP). O-GlcNAcylation regulates a wide spectrum of substrates including many proteins involved in epigenetic modification. Like epigenetic modifications, abnormality of O-GlcNAcylation is also common in cancer. Studies have revealed substantial impact on HBP enzymes and OGT/OGA by oncogenic signals. In this review, we will first summarize how oncogenic signals regulate HBP enzymes, OGT and OGA in cancer. We will then integrate this knowledge with the up to date understanding how O-GlcNAcylation regulates epigenetic machinery. With this, we propose a signal axis from oncogenic signals through O-GlcNAcylation dysregulation to epigenetic abnormality in cancer. Further elucidation of this axis will not only advance our understanding of cancer biology but also provide new revenues towards cancer therapy.
表观遗传修饰的普遍失调在癌症中起着关键作用。靶向表观遗传异常是癌症治疗的一种新策略。了解传统致癌因素如何导致表观遗传异常具有重要的基础和转化价值。O-连接的N-乙酰葡糖胺化（O-GlcNAcylation）是一种影响生理和病理生理的蛋白质修饰。在哺乳动物中，O-GlcNAcylation由单一酶O-连接的N-乙酰葡糖胺转移酶（OGT）催化，并由单一酶O-连接的N-乙酰葡糖胺酶（OGA）去除。O-GlcNAcylation受己糖胺生物合成途径（HBP）中一系列酶促反应产生的供体UDP-GlcNAc可用性的影响。O-GlcNAcylation调节广泛的底物，包括许多参与表观遗传修饰的蛋白质。与表观遗传修饰一样，O-GlcNAcylation异常在癌症中也很常见。研究表明致癌信号对HBP酶和OGT/OGA有重大影响。在这篇综述中，我们将首先总结致癌信号如何在癌症中调节HBP酶、OGT和OGA。然后，我们将把这些知识与目前对O-GlcNAcylation如何调节表观遗传机制的理解相结合。据此，我们提出了一条从致癌信号通过O-GlcNAcylation失调到癌症表观遗传异常的信号轴。进一步阐明这条轴不仅将推进我们对癌症生物学的理解，还将为癌症治疗提供新的途径。
