Loss of TET2 Tips the Scales Toward Tumorigenesis

The study by Boudra et al. demonstrates that the loss of the DNA demethylase TET2 significantly increases the risk and severity of squamous cell carcinomas (SCC) in both skin and oral epithelia. Using a mouse model, the researchers showed that epithelial-specific deletion of Tet2, especially when combined with the carcinogen 4-NQO or TP53 deletion, leads to a higher number and grade of SCC tumors. Mechanistic studies indicated that TET2 loss results in transcriptional dysregulation, including downregulation of epidermal differentiation genes and upregulation of genes associated with hair follicle cells and basal epidermal stem cells. These findings underscore TET2's tumor-suppressive role and suggest potential therapeutic strategies, such as ascorbic acid or EZH2 inhibitors, for TET2-deficient SCCs.