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

Volume 13 Issue 6

Jun. 2023

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Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(6): 590-602

Zhiwei Zheng, Benyu Nan, Chang Liu, Dongmei Tang, Wen Li, Liping Zhao, Guohui Nie, Yingzi He. Inhibition of histone methyltransferase PRMT5 attenuates cisplatin-induced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway[J]. Journal of Pharmaceutical Analysis, 2023, 13(6): 590-602. doi: 10.1016/j.jpha.2023.04.014

Citation:

Zhiwei Zheng, Benyu Nan, Chang Liu, Dongmei Tang, Wen Li, Liping Zhao, Guohui Nie, Yingzi He. Inhibition of histone methyltransferase PRMT5 attenuates cisplatin-induced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway[J]. Journal of Pharmaceutical Analysis, 2023, 13(6): 590-602. doi: 10.1016/j.jpha.2023.04.014

Citation:

Zhiwei Zheng, Benyu Nan, Chang Liu, Dongmei Tang, Wen Li, Liping Zhao, Guohui Nie, Yingzi He. Inhibition of histone methyltransferase PRMT5 attenuates cisplatin-induced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway[J]. Journal of Pharmaceutical Analysis, 2023, 13(6): 590-602. doi: 10.1016/j.jpha.2023.04.014

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

doi: 10.1016/j.jpha.2023.04.014

a. 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;
b. Department of Otorhinolaryngology-Head and Neck Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China;
c. Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China;
d. Department of Otolaryngology, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, Guangdong, China

Funds:

This work was supported by grants from the National Natural Science Foundation of China (Grant Nos.: 82271158, 82192865, and 82071045), and Wenzhou Municipal Science and Technology Research Program (Grant No.: 2021Y0681).

Received Date: Dec. 22, 2022
Accepted Date: Apr. 21, 2023
Rev Recd Date: Apr. 19, 2023
Publish Date: Apr. 26, 2023

Abstract

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

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References(58)

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