Inhibition of Protein arginine methyltransferase 6 reduces reactive oxygen species production and attenuates aminoglycoside- and cisplatin-induced hair cell death

Our findings suggested that PRMT6 might serve as a new therapeutic target to prevent hearing loss caused by aminoglycoside- and cisplatin-induced ototoxicity by preventing ROS formation and modulating the mitochondria-related damage and apoptosis.

In this study, we investigated the role of protein arginine methyltransferase 6 (PRMT6) in aminoglycoside- and cisplatin-induced hair cell loss by using EPZ020411, a selective small molecule PRMT6 inhibitor, in vitro in neonatal mouse cochlear explants and in vivo in C57BL/6 mice. We also took advantage of the HEI-OC1 cell line to evaluate the anti-apoptosis effects of PRMT6 knockdown on cisplatin-induced ototoxicity. Apoptotic cells were identified using cleaved caspase-3 staining and TUNEL assay. The levels of reactive oxygen species (ROS) were evaluated by DCFH-DA and cellROX green staining. The mitochondrial membrane potential (ΔΨm) were determined by JC-1, TMRM, and rhodamine 123 staining.

We found that EPZ020411 significantly alleviated neomycin- and cisplatin-induced cell apoptosis and increased hair cell survival. Moreover, pretreatment with EPZ020411 could attenuate neomycin- and cisplatin-induced hearing loss in vivo. Mechanistic studies revealed that inhibition of PRMT6 could reverse the increased expression of caspase-3 and cytochrome c translocation, mitochondrial dysfunction, increased accumulation of ROS, and activation of cell apoptosis after cisplatin injury. Conclusions: Our findings suggested that PRMT6 might serve as a new therapeutic target to prevent hearing loss caused by aminoglycoside- and cisplatin-induced ototoxicity by preventing ROS formation and modulating the mitochondria-related damage and apoptosis.