Inhibition of PRMT6 reduces neomycin-induced inner ear hair cell injury through the restraint of FoxG1 arginine methylation.

OBJECTIVE

Hair cells in the inner ear have been demonstrated to be sensitive to the ototoxicity from some beneficial pharmaceutical drugs. This study aimed to explore the role of protein arginine methyltransferase 6 (PRMT6) in the process of neomycin-induced hearing loss and the underlying mechanism.

METHODS

The neomycin-induced hearing loss mouse model and hair cell injury in vitro model were established. We took advantage of the HEI-OC1 cell line to evaluate PRMT6 expression in neomycin-induced hair cells, and the effect of PRMT6 on mitochondrial function and FoxG1 arginine methylation. Apoptotic cells were assessed and apoptotic marker cleaved caspase-3 level was detected. Reactive oxygen species (ROS) level and mitochondrial membrane potential (MMP) were subsequently measured.

RESULT

The result showed that PRMT6 was significantly upregulated in neomycin-induced HEI-OC-1 cells, and PRMT6 silencing prevented MMP loss, reduced ROS production, as well as decreased cell apoptosis under neomycin treatment. Further results showed that FoxG1 was downregulated in neomycin-induced HEI-OC-1 cells, and PRMT6 promoted the FoxG1-mediated luciferase activity, while PRMT6 silencing reversed this effect. Mechanistic experiments revealed that PRMT6 silencing reduced the arginine methylation level of FoxG1 protein. In vivo, neomycin-induced upregulation of hearing thresholds and increased cell apoptosis, whereas PRMT6 inhibitor partly reversed these effects.

CONCLUSION

Our findings suggested that inhibition of PRMT6 reduced neomycin-induced inner ear hair cell injury through the restraint of FoxG1 arginine methylation.