Abstract
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 TETs 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.
Highlights
An estimated 1.8 million new cancer cases were diagnosed in the United States in2020 [1,2]
Active demethylation is achieved by ten-eleven translocation (TET) enzymes whereby ten-eleven translocation 1 (TET1), TET2, and TET3 sequentially oxidize 5-mC to 5-hmC, 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC), followed by replication-dependent dilution or thymine DNA glycosylase (TDG)-dependent base excision repair (BER) [21,38]
TET1 and TET2 are highly expressed in ESCs, which is consistent with the abundance of 5-hmC in these cells [120]
Summary
An estimated 1.8 million new cancer cases were diagnosed in the United States in. 2020 [1,2]. An estimated 1.8 million new cancer cases were diagnosed in the United States in. Cancer is the second leading cause of death in the United States, with an estimated toll of 606,520 American lives in 2020 [2,3]. Cigarette smoking alone is responsible for approximately 30% of all cancer deaths in the United States [1,3]. Epigenetic mechanisms have come to the forefront of cancer research, owing to their ability to initiate the disease as well as modulate its clinical course and progression [10,15,16]. Given the extensive body of research on DNA hydroxymethylation and smoking-associated cancers, we have highlighted examples of studies on lung, bladder, and colorectal cancers to summarize the current state of knowledge, outstanding questions, and future directions in this ever-evolving field
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