Inhibition of histone methyltransferase PRMT5 attenuates cisplatin-induced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway

Zhiwei Zheng; Benyu Nan; Chang Liu; Dongmei Tang; Wen Li; Liping Zhao; Guohui Nie; Yingzi He

doi:10.1016/j.jpha.2023.04.014

Inhibition of histone methyltransferase PRMT5 attenuates cisplatin-induced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway

J Pharm Anal. 2023 Jun;13(6):590-602. doi: 10.1016/j.jpha.2023.04.014. Epub 2023 Apr 26.

Authors

Zhiwei Zheng¹, Benyu Nan², Chang Liu³, Dongmei Tang¹, Wen Li¹, Liping Zhao¹, Guohui Nie⁴, Yingzi He¹

Affiliations

¹ ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, NHC Key Laboratory of Hearing Medicine (Fudan University), Fudan University, Shanghai, 200031, China.
² Department of Otorhinolaryngology-Head and Neck Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
³ Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
⁴ Department of Otolaryngology, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, Guangdong, China.

Abstract

This study aimed to evaluate the therapeutic potential of inhibiting protein arginine methyltransferase 5 (PRMT5) in cisplatin-induced hearing loss. The effects of PRMT5 inhibition on cisplatin-induced auditory injury were determined using immunohistochemistry, apoptosis assays, and auditory brainstem response. The mechanism of PRMT5 inhibition on hair cell survival was assessed using RNA-seq and Cleavage Under Targets and Tagment-quantitative polymerase chain reaction (CUT&Tag-qPCR) analyses in the HEI-OC1 cell line. Pharmacological inhibition of PRMT5 significantly alleviated cisplatin-induced damage to hair cells and spiral ganglion neurons in the cochlea and decreased apoptosis by protecting mitochondrial function and preventing the accumulation of reactive oxygen species. CUT&Tag-qPCR analysis demonstrated that inhibition of PRMT5 in HEI-OC1 cells reduced the accumulation of H4R3me2s/H3R8me2s marks at the promoter region of the Pik3ca gene, thus activating the expression of Pik3ca. These findings suggest that PRMT5 inhibitors have strong potential as agents against cisplatin-induced ototoxicity and can lay the foundation for further research on treatment strategies of hearing loss.

Keywords: Cisplatin; Hair cell; Hearing loss; LLY-283; Protein arginine methyltransferase 5 (PRMT5); Spiral ganglion neuron.