Modulating DNA Methylation in Mature Hair Cells to Mitigate Cisplatin-Induced Hearing Loss: A Review

Cisplatin-induced hearing loss (CIHL) is a debilitating side effect in cancer patients undergoing chemotherapy. So far, epigenetic studies in the inner ear have largely focused on developmental biology to regenerate hair cells. In post-mitotic hair cells, on the other hand, DNA methylation regulates transcriptomic response to external stimuli. Adult mammalian hair cells are locked in the G0 phase, and passive demethylation via DNA replication does not occur under normal physiological conditions. However, external stimuli such as cisplatin can aberrantly upregulate DNMT methyltransferases (DNMTs), resulting in promoter methylation and silencing protective genes. From this angle, DNMTs modulation is an attractive therapeutic strategy to protect hearing during chemotherapy. Recent studies suggest that non-nucleoside inhibitors such as RG108 and natural polyphenolic compounds downregulate DNMTs, and at the same time, protect auditory cells. These compounds function via the inhibition of the DNMT catalytic site but can also act through downregulating DNMT1 and DNMT3A/B at mRNA and protein levels. Polyphenols are also antioxidants, decreasing reactive oxygen species, thereby increasing cell survival. Furthermore, it is suggested that upregulating TET-mediated active demethylation can be another angle to modify DNA methylation in cancer and CIHL models. However, functional DNA methylation should be distinguished from non-functional, passenger DNA methylation to elucidate the compounds’ otoprotective effects. In addition, the candidate compounds should not interfere with cisplatin’s antitumor effect. In this review, we investigate the relationship between DNA methylation and CIHL in the post-mitotic inner ear and evaluate the therapeutic potential of candidate DNMT inhibitors.