Department of Population & Public Health Sciences, USC Keck School of Medicine, University of Southern California, M/C 9603, Los Angeles, CA 90033, USA.
Int J Mol Sci. 2022 Feb 28;23(5):2657. doi: 10.3390/ijms23052657.
5-hydroxymethylcytosine (5-hmC) was first detected in mammalian DNA five decades ago. However, it did not take center stage in the field of epigenetics until 2009, when ten-eleven translocation 1 (TET1) was found to oxidize 5-methylcytosine to 5-hmC, thus offering a long-awaited mechanism for active DNA demethylation. Since then, a remarkable body of research has implicated DNA hydroxymethylation in pluripotency, differentiation, neural system development, aging, and pathogenesis of numerous diseases, especially cancer. Here, we focus on DNA hydroxymethylation in smoking-associated carcinogenesis to highlight the diagnostic, therapeutic, and prognostic potentials of this epigenetic mark. We describe the significance of 5-hmC in DNA demethylation, the importance of substrates and cofactors in TET-mediated DNA hydroxymethylation, the regulation of and related genes (isocitrate dehydrogenases, fumarate hydratase, and succinate dehydrogenase), the cell-type dependency and genomic distribution of 5-hmC, and the functional role of 5-hmC in the epigenetic regulation of transcription. We showcase examples of studies on three major smoking-associated cancers, including lung, bladder, and colorectal cancers, to summarize the current state of knowledge, outstanding questions, and future direction in the field.
5-羟甲基胞嘧啶（5-hmC）在五十年前首次在哺乳动物 DNA 中被发现。然而，直到 2009 年 ten-eleven 易位 1（TET1）被发现将 5-甲基胞嘧啶氧化为 5-hmC，为活跃的 DNA 去甲基化提供了一个期待已久的机制，它才在表观遗传学领域中占据中心地位。从那时起，大量研究表明 DNA 羟甲基化与多能性、分化、神经系统发育、衰老和许多疾病的发病机制有关，尤其是癌症。在这里，我们重点关注与吸烟相关的致癌作用中的 DNA 羟甲基化，以突出该表观遗传标记的诊断、治疗和预后潜力。我们描述了 5-hmC 在 DNA 去甲基化中的意义、TET 介导的 DNA 羟甲基化中底物和辅助因子的重要性、 和相关基因（异柠檬酸脱氢酶、延胡索酸水合酶和琥珀酸脱氢酶）的调节、5-hmC 的细胞类型依赖性和基因组分布，以及 5-hmC 在转录的表观遗传调控中的功能作用。我们展示了三个主要的与吸烟相关的癌症（包括肺癌、膀胱癌和结直肠癌）的研究示例，以总结该领域目前的知识状况、悬而未决的问题和未来的方向。
