DNA Hydroxymethylation in Smoking-Associated Cancers

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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 translocation ten-eleven 1 (TET1) was found to oxidize 5-methylcytosine to 5-hmC, providing thus 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 the pathogenesis of many 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 importance of 5-hmC in DNA demethylation, the importance of substrates and cofactors in TET-mediated DNA hydroxymethylation, the regulation of TFW and related genes (isocitrate dehydrogenases, fumarate hydratase, and succinate dehydrogenase), the cell type dependence and genomic distribution of 5-hmC, and the functional role of 5-hmC in the epigenetic regulation of transcription. We present examples of studies on three major cancers associated with smoking, including lung, bladder, and colorectal cancers, to summarize the current state of knowledge, outstanding questions, and future direction in the field.

PMID:35269796 | PMC: PMC8910185 | DOI: 10.3390/ijms23052657

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