Inhibition of histone methyltransferase PRMT5 attenuates cisplatin-induced hearing loss through the PI3K/Akt-mediated mitochondrial apoptotic pathway
10.1016/j.jpha.2023.04.014
- Author:
Zhiwei ZHENG
1
;
Benyu NAN
;
Chang LIU
;
Dongmei TANG
;
Wen LI
;
Liping ZHAO
;
Guohui NIE
;
Yingzi HE
Author Information
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
- Keywords:
Protein arginine methyltransferase 5(PRMT5);
LLY-283;
Cisplatin;
Hearing loss;
Hair cell;
Spiral ganglion neuron
- From:
Journal of Pharmaceutical Analysis
2023;13(6):590-602
- CountryChina
- Language:Chinese
-
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.
