Theranostics 2020; 10(1):133-150. doi:10.7150/thno.37362 This issue

Research Paper

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

Yingzi He1*, Wen Li1*, Zhiwei Zheng2*, Liping Zhao1, Wenyan Li1, Yunfeng Wang1✉, Huawei Li1,3,4,5✉

1. Department of ENT institute and Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai, 200032, PR China
2. Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, 361003, China
3. Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, PR China
4. Shanghai Engineering Research Centre of Cochlear Implant, Shanghai, 200031, PR China
5. The Institutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China
*Yingzi He, Wen Li and Zhiwei Zheng contributed equally to this work.

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Citation:
He Y, Li W, Zheng Z, Zhao L, Li W, Wang Y, Li H. Inhibition of Protein arginine methyltransferase 6 reduces reactive oxygen species production and attenuates aminoglycoside- and cisplatin-induced hair cell death. Theranostics 2020; 10(1):133-150. doi:10.7150/thno.37362. Available from https://www.thno.org/v10p0133.htm

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Abstract

Graphic abstract

Hair cells in the inner ear have been shown to be susceptible to ototoxicity from some beneficial pharmaceutical drugs, such as aminoglycosides and cisplatin. Thus, there is great interest in discovering new targets or compounds that protect hair cells from these ototoxic drugs. Epigenetic regulation is closely related to inner ear development; however, little is known about epigenetic regulation in the process of ototoxic drugs-induced hearing loss.

Methods: 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.

Results: 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.

Keywords: Aminoglycoside, cisplatin, ototoxicity, mitochondrial dysfunction, hair cell, protectio