Oxidative Stress, Nrf2, and Epigenetic Modification Contribute to Anticancer Drug Resistance

Abstract

Nuclear factor E2-related factor 2 (Nrf2), a transcription factor, controls the expression of genes encoding cytoprotective proteins, including antioxidant enzymes that combat oxidative and electrophilic stress to maintain redox homeostasis. However, recent studies demonstrated that, in cancer, aberrant activation of Nrf2 by epigenetic alterations promotes high expression of cytoprotective proteins, which can decrease the efficacy of anticancer drugs used for chemotherapy. In this review, we summarize recent findings regarding the relationship between oxidative stress, Nrf2, epigenetic modification, and anticancer drug resistance, which should aid in development of new strategies to improve chemotherapeutic efficacy.

Keywords: Anticancer drug resistance; Epigenetic modification; Nrf2 transcription factor; Oxidative stress.

Fig. 1

Oxidative stress status in anticancer drug resistance (8). Drug-induced persistent oxidative stress can be overcome by increasing genomic instability and by redox adaption. Both processes are implicated in cancer progression and drug resistance.

Fig. 2

Cytosine methylation and demethylation (18,19). DNMTs catalyze conversion of cytosine into 5-mC. TET proteins can iteratively oxidize 5-mC to 5-hmC, 5-fC, and 5-caC. Thymine DNA glycosylase (TDG) can decarboxylate either 5-fC or 5-caC and replace it with an unmodified cytosine through base excision repair (BER), completing the cycle of dynamic cytosine removal.

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.