Skip to main content
SpringerLink
Log in

YTHDF1 Protects Auditory Hair Cells from Cisplatin-Induced Damage by Activating Autophagy via the Promotion of ATG14 Translation

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

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.

References

  1. Fu X, Li P, Zhang L, Song Y, An Y, Zhang A et al (2022) Activation of Rictor/mTORC2 signaling acts as a pivotal strategy to protect against sensorineural hearing loss. Proc Natl Acad Sci U S A 119(10):e2107357119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang M, Dong Y, Gao S, Zhong Z, Cheng C, Qiang R et al (2022) Hippo/YAP signaling pathway protects against neomycin-induced hair cell damage in the mouse cochlea. Cell Mol Life Sci 79(2):79

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zhong Z, Fu X, Li H, Chen J, Wang M, Gao S et al (2020) Citicoline Protects Auditory Hair Cells Against Neomycin-Induced Damage. Front Cell Dev Biol 8:712

    Article  PubMed  PubMed Central  Google Scholar 

  4. Li A, You D, Li W, Cui Y, He Y, Li W et al (2018) Novel compounds protect auditory hair cells against gentamycin-induced apoptosis by maintaining the expression level of H3K4me2. Drug Deliv 25(1):1033–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Guo L, Cao W, Niu Y, He S, Chai R, Yang J (2021) Autophagy Regulates the Survival of Hair Cells and Spiral Ganglion Neurons in Cases of Noise, Ototoxic Drug, and Age-Induced Sensorineural Hearing Loss. Front Cell Neurosci 15:760422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jiang P, Ma X, Han S, Ma L, Ai J, Wu L et al (2022) Characterization of the microRNA transcriptomes and proteomics of cochlear tissue-derived small extracellular vesicles from mice of different ages after birth. Cell Mol Life Sci 79(3):154

    Article  CAS  PubMed  Google Scholar 

  7. He ZH, Li M, Fang QJ, Liao FL, Zou SY, Wu X et al (2021) FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway. Autophagy 17(12):4341–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhou H, Qian X, Xu N, Zhang S, Zhu G, Zhang Y et al (2020) Disruption of Atg7-dependent autophagy causes electromotility disturbances, outer hair cell loss, and deafness in mice. Cell Death Dis 11(10):913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cheng C, Wang Y, Guo L, Lu X, Zhu W, Muhammad W et al (2019) Age-related transcriptome changes in Sox2+ supporting cells in the mouse cochlea. Stem Cell Res Ther 10(1):365

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fu X, An Y, Wang H, Li P, Lin J, Yuan J et al (2021) Deficiency of Klc2 Induces Low-Frequency Sensorineural Hearing Loss in C57BL/6 J Mice and Human. Mol Neurobiol 58(9):4376–91

    Article  CAS  PubMed  Google Scholar 

  11. Cheng C, Hou Y, Zhang Z, Wang Y, Lu L, Zhang L et al (2021) Disruption of the autism-related gene Pak1 causes stereocilia disorganization, hair cell loss, and deafness in mice. J Genet Genomics 48(4):324–32

    Article  CAS  PubMed  Google Scholar 

  12. Lv J, Fu X, Li Y, Hong G, Li P, Lin J et al (2021) Deletion of Kcnj16 in Mice Does Not Alter Auditory Function. Front Cell Dev Biol 9:630361

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhang S, Dong Y, Qiang R, Zhang Y, Zhang X, Chen Y et al (2021) Characterization of Strip1 Expression in Mouse Cochlear Hair Cells. Front Genet 12:625867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Qian F, Wang X, Yin Z, Xie G, Yuan H, Liu D et al (2020) The slc4a2b gene is required for hair cell development in zebrafish. Aging (Albany NY) 12(19):18804–21

    Article  CAS  Google Scholar 

  15. He ZH, Zou SY, Li M, Liao FL, Wu X, Sun HY et al (2020) The nuclear transcription factor FoxG1 affects the sensitivity of mimetic aging hair cells to inflammation by regulating autophagy pathways. Redox Biol 28:101364

    Article  CAS  PubMed  Google Scholar 

  16. Han S, Xu Y, Sun J, Liu Y, Zhao Y, Tao W et al (2020) Isolation and analysis of extracellular vesicles in a Morpho butterfly wing-integrated microvortex biochip. Biosens Bioelectron 154:112073

    Article  CAS  PubMed  Google Scholar 

  17. Zhang Y, Li Y, Fu X, Wang P, Wang Q, Meng W et al (2021) The Detrimental and Beneficial Functions of Macrophages After Cochlear Injury. Front Cell Dev Biol 9:631904

    Article  PubMed  PubMed Central  Google Scholar 

  18. Astolfi L, Ghiselli S, Guaran V, Chicca M, Simoni E, Olivetto E et al (2013) Correlation of adverse effects of cisplatin administration in patients affected by solid tumours: a retrospective evaluation. Oncol Rep 29(4):1285–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gentilin E, Minoia M, Bondanelli M, Tagliati F, Degli UE, Zatelli MC (2017) Growth Hormone differentially modulates chemoresistance in human endometrial adenocarcinoma cell lines. Endocrine 56(3):621–32

    Article  CAS  PubMed  Google Scholar 

  20. Paken J, Govender CD, Pillay M, Sewram V (2016) Cisplatin-Associated Ototoxicity: A Review for the Health Professional. J Toxicol 2016:1809394

    Article  PubMed  PubMed Central  Google Scholar 

  21. Coradini PP, Cigana L, Selistre SG, Rosito LS, Brunetto AL (2007) Ototoxicity from cisplatin therapy in childhood cancer. J Pediatr Hematol Oncol 29(6):355–60

    Article  CAS  PubMed  Google Scholar 

  22. Knight KR, Kraemer DF, Neuwelt EA (2005) Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol 23(34):8588–96

    Article  PubMed  Google Scholar 

  23. Li Y, Womer RB, Silber JH (2004) Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose. Eur J Cancer 40(16):2445–51

    Article  CAS  PubMed  Google Scholar 

  24. Gentilin E, Simoni E, Candito M, Cazzador D, Astolfi L (2019) Cisplatin-Induced Ototoxicity: Updates on Molecular Targets. Trends Mol Med 25(12):1123–32

    Article  CAS  PubMed  Google Scholar 

  25. Sheth S, Mukherjea D, Rybak LP, Ramkumar V (2017) Mechanisms of Cisplatin-Induced Ototoxicity and Otoprotection. Front Cell Neurosci 11:338

    Article  PubMed  PubMed Central  Google Scholar 

  26. Li H, Song Y, He Z, Chen X, Wu X, Li X et al (2018) Meclofenamic Acid Reduces Reactive Oxygen Species Accumulation and Apoptosis, Inhibits Excessive Autophagy, and Protects Hair Cell-Like HEI-OC1 Cells From Cisplatin-Induced Damage. Front Cell Neurosci 12:139

    Article  PubMed  PubMed Central  Google Scholar 

  27. Fu X, Wan P, Li P, Wang J, Guo S, Zhang Y et al (2021) Mechanism and Prevention of Ototoxicity Induced by Aminoglycosides. Front Cell Neurosci 15:692762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. He Z, Guo L, Shu Y, Fang Q, Zhou H, Liu Y et al (2017) Autophagy protects auditory hair cells against neomycin-induced damage. Autophagy 13(11):1884–904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen X, Sun YZ, Liu H, Zhang L, Li JQ, Meng J (2019) RNA methylation and diseases: experimental results, databases, Web servers and computational models. Brief Bioinform 20(3):896–917

    Article  CAS  PubMed  Google Scholar 

  30. Chen X, Wang J, Tahir M, Zhang F, Ran Y, Liu Z et al (2021) Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases. Cell Biosci 11(1):147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jin S, Zhang X, Miao Y, Liang P, Zhu K, She Y et al (2018) m(6)A RNA modification controls autophagy through upregulating ULK1 protein abundance. Cell Res 28(9):955–7

    Article  PubMed  PubMed Central  Google Scholar 

  32. Shi H, Zhang X, Weng YL, Lu Z, Liu Y, Lu Z et al (2018) m(6)A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature 563(7730):249–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Teitz T, Fang J, Goktug AN, Bonga JD, Diao S, Hazlitt RA et al (2018) CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. J Exp Med 215(4):1187–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Babolmorad G, Latif A, Domingo IK, Pollock NM, Delyea C, Rieger AM et al (2021) Toll-like receptor 4 is activated by platinum and contributes to cisplatin-induced ototoxicity. Embo Rep 22(5):e51280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pang J, Xiong H, Zhan T, Cheng G, Jia H, Ye Y et al (2018) Sirtuin 1 and Autophagy Attenuate Cisplatin-Induced Hair Cell Death in the Mouse Cochlea and Zebrafish Lateral Line. Front Cell Neurosci 12:515

    Article  CAS  PubMed  Google Scholar 

  36. Song H, Feng X, Zhang H, Luo Y, Huang J, Lin M et al (2019) METTL3 and ALKBH5 oppositely regulate m(6)A modification of TFEB mRNA, which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes. Autophagy 15(8):1419–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang X, Wu R, Liu Y, Zhao Y, Bi Z, Yao Y et al (2020) m(6)A mRNA methylation controls autophagy and adipogenesis by targeting Atg5 and Atg7. Autophagy 16(7):1221–35

    Article  CAS  PubMed  Google Scholar 

  38. Liu W, Xu L, Wang X, Zhang D, Sun G, Wang M et al (2021) PRDX1 activates autophagy via the PTEN-AKT signaling pathway to protect against cisplatin-induced spiral ganglion neuron damage. Autophagy 17(12):4159–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kimura S, Noda T, Yoshimori T (2007) Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3(5):452–60

    Article  CAS  PubMed  Google Scholar 

  40. Li Q, Ni Y, Zhang L, Jiang R, Xu J, Yang H et al (2021) HIF-1alpha-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation. Signal Transduct Target Ther 6(1):76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhou B, Liu C, Xu L, Yuan Y, Zhao J, Zhao W et al (2020) N6 -methyladenosine Reader Protein Ythdc2 Suppresses Liver Steatosis via Regulation of mRNA Stability of Lipogenic Genes. Hepatology (Baltimore, Md.) 73(1).

  42. Chen Y, Wang J, Xu D, Xiang Z, Ding J, Yang X et al (2021) m(6)A mRNA methylation regulates testosterone synthesis through modulating autophagy in Leydig cells. Autophagy 17(2):457–75

    Article  CAS  PubMed  Google Scholar 

  43. Berulava T, Buchholz E, Elerdashvili V, Pena T, Islam MR, Lbik D et al (2020) Changes in m6A RNA methylation contribute to heart failure progression by modulating translation. Eur J Heart Fail 22(1):54–66

    Article  CAS  PubMed  Google Scholar 

  44. Liu T, Wei Q, Jin J, Luo Q, Liu Y, Yang Y et al (2020) The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res 48(7):3816–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Aguilo F, Zhang F, Sancho A, Fidalgo M, Di Cecilia S, Vashisht A et al (2015) Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming. Cell Stem Cell 17(6):689–704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hess ME, Hess S, Meyer KD, Verhagen LA, Koch L, Bronneke HS et al (2013) The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci 16(8):1042–8

    Article  CAS  PubMed  Google Scholar 

  47. Xu K, Yang Y, Feng GH, Sun BF, Chen JQ, Li YF et al (2017) Mettl3-mediated m(6)A regulates spermatogonial differentiation and meiosis initiation. Cell Res 27(9):1100–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li HB, Tong J, Zhu S, Batista PJ, Duffy EE, Zhao J et al (2017) m(6)A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 548(7667):338–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Xiao W, Adhikari S, Dahal U, Chen YS, Hao YJ, Sun BF et al (2016) Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing. Mol Cell 61(4):507–19

    Article  CAS  PubMed  Google Scholar 

  50. Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H et al (2015) N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell 161(6):1388–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Merkurjev D, Hong WT, Iida K, Oomoto I, Goldie BJ, Yamaguti H et al (2018) Synaptic N(6)-methyladenosine (m(6)A) epitranscriptome reveals functional partitioning of localized transcripts. Nat Neurosci 21(7):1004–14

    Article  CAS  PubMed  Google Scholar 

  52. Weng YL, Wang X, An R, Cassin J, Vissers C, Liu Y et al (2018) Epitranscriptomic m(6)A Regulation of Axon Regeneration in the Adult Mammalian Nervous System. Neuron 97(2):313–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shi Y, Fan S, Wu M, Zuo Z, Li X, Jiang L et al (2019) YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression. Nat Commun 10(1):4892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Levano S, Bodmer D (2015) Loss of STAT1 protects hair cells from ototoxicity through modulation of STAT3, c-Jun, Akt, and autophagy factors. Cell Death Dis 6:e2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Fujimoto C, Iwasaki S, Urata S, Morishita H, Sakamaki Y, Fujioka M et al (2017) Autophagy is essential for hearing in mice. Cell Death Dis 8(5):e2780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yin H, Yang Q, Cao Z, Li H, Yu Z, Zhang G et al (2018) Activation of NLRX1-mediated autophagy accelerates the ototoxic potential of cisplatin in auditory cells. Toxicol Appl Pharmacol 343:16–28

    Article  CAS  PubMed  Google Scholar 

  57. Lin Z, Tong MH (1862) 2019 m(6)A mRNA modification regulates mammalian spermatogenesis. Biochim Biophys Acta Gene Regul Mech 3:403–11

    Google Scholar 

  58. Lin Z, Niu Y, Wan A, Chen D, Liang H, Chen X et al (2020) RNA m(6) A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy. Embo J 39(12):e103181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Park J, Seo M, Jung CH, Grunwald D, Stone M, Otto NM et al (2018) ULK1 phosphorylates Ser30 of BECN1 in association with ATG14 to stimulate autophagy induction. Autophagy 14(4):584–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

Author notes

  1. Yuyu Huang, Dekun Gao, and Yan Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Yuyu Huang, Dekun Gao, Yan Wu, Lianhua Sun, Jianyong Chen, Junmin Chen, Jun Yang & Shuna Li

  2. Shanghai Jiaotong University School of Medicine Ear Institute, Shanghai, China

    Yuyu Huang, Dekun Gao, Yan Wu, Lianhua Sun, Jianyong Chen, Junmin Chen, Jun Yang & Shuna Li

  3. Shanghai Key Laboratory of Translational Medicine On Ear and Nose Diseases, Shanghai, China

    Yuyu Huang, Dekun Gao, Yan Wu, Lianhua Sun, Jianyong Chen, Junmin Chen, Jun Yang & Shuna Li

  4. School of Life Science and Technology, ShanghaiTech University, Shanghai, People’s Republic of China

    Xingxu Huang

Authors
  1. Yuyu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dekun Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lianhua Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianyong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Junmin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xingxu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shuna Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding authors

Correspondence to Jun Yang or Shuna Li.

Ethics declarations

Ethics Approval

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.).

Consent to Participate and Consent to Publish

All research did not involve human subjects.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-03021-z

Keywords

Search

Navigation