Abstract
N6-methyladenosine (m6A) has been recognized as a common type of post-transcriptional epigenetic modification. m6A modification and YTHDF1, one of its reader proteins, have been documented to play a pivotal role in numerous human diseases via regulating mRNA splicing, translation, stability, and subcellular localization. The chemotherapeutic drug cisplatin (CDP) can damage sensory hair cells (HCs) and result in permanent sensorineural hearing loss. However, whether YTHDF1-mediated modification of mRNA is potentially involved in CDP-induced injury in sensory hair cells was not fully clarified. This study investigated the potential mechanisms for the modification of YTHDF1 in CDP-induced damage in HCs. Here, we discovered that YTHDF1's expression level statistically increased significantly after treating with CDP. Apoptosis and cell death of HCs induced by CDP were exacerbated after the knockdown of YTHDF1, while overexpression of YTHDF1 in HCs alleviated their injury induced by CDP. Moreover, YTHDF1 expression correlated with cisplatin-induced autophagy with statistical significance in HCs; namely, YTHDF1’s overexpression enhanced the activation of autophagy, while its deficiency suppressed autophagy and, at the same time, increased the loss of HCs after CDP damage. WB analysis and qRT-PCR results of autophagy-related genes indicated that YTHDF1 promoted the translation of autophagy-related genes ATG14, thus boosting autophagy. Therefore, CDP-induced YTHDF1 expression protected HCs against CDP-induced apoptosis by upregulating the translation of autophagy-related genes ATG14, along with enhancing autophagy. Based on these findings, it can be inferred that YTHDF1 is potentially a target for ameliorating drug-induced HCs damage through m6A modification.
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Data Availability
Data are available on request from the authors. The data that support the findings of this study are available from the corresponding author, Li Shuna, upon request.
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Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (Grant No. 81873698, 82171135)
Funding
This work was supported by a grant from the National Natural Science Foundation of China, which was awarded to Professor Shuna Li (Grant/Award Numbers: 82171135) and Professor Jun Yang (Grant/Award Numbers: 81873698).
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HYY, GDK, and WY contributed equally to this manuscript. HYY, YJ, and LSN contributed to the conception and design of the study. HYY, GDK, and CJM organized the methods and database. HYY, SLH, and CJY performed the statistical analysis. HYY wrote the first draft of the manuscript. GDK and WY wrote sections of the manuscript. HXX provided the YTHDF1-knockout mice. All authors contributed to manuscript revision, read, and approved the submitted version.
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For the design of the experimental animals involved in the study, the researchers will follow the principles of "Replacement, Reduction and Refinement." Approval was granted by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Approval No, XHEC-F-2022–056.).
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Huang, Y., Gao, D., Wu, Y. et al. YTHDF1 Protects Auditory Hair Cells from Cisplatin-Induced Damage by Activating Autophagy via the Promotion of ATG14 Translation. Mol Neurobiol 59, 7134–7151 (2022). https://doi.org/10.1007/s12035-022-03021-z
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DOI: https://doi.org/10.1007/s12035-022-03021-z