Fig. 3.

Model: the roles of DNA demethylation and histone methylation in the mechanism of resistance to 5-FU (26,27). 5-FU induces oxidative stress via generation of ROS, which increase TET1 activity. Induction of TET1 leads to activation of Nrf2, ultimately causing drug resistance. Moreover, oxidative stress-activated TET1 recruits OGT to the Nrf2 promoter. OGT GlcNAcylates HCF1, a component of the MLL/COMPASS-like complex. This complex methylates H3K4, resulting in transcriptional activation of Nrf2, leading to chemo-resistance.