Role and mechanism of FOXG1-related epigenetic modifications in cisplatin-induced hair cell damage

Yu-Rong Mu; Sheng-Yu Zou; Ming Li; Yan-Yan Ding; Xiang Huang; Zu-Hong He; Wei-Jia Kong

doi:10.3389/fnmol.2023.1064579

Role and mechanism of FOXG1-related epigenetic modifications in cisplatin-induced hair cell damage

Front Mol Neurosci. 2023 Apr 26:16:1064579. doi: 10.3389/fnmol.2023.1064579. eCollection 2023.

Authors

Yu-Rong Mu^#¹, Sheng-Yu Zou^#², Ming Li¹, Yan-Yan Ding¹, Xiang Huang¹, Zu-Hong He², Wei-Jia Kong¹

Affiliations

¹ Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Otorhinolaryngology-Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.

^# Contributed equally.

Abstract

Cisplatin is widely used in clinical tumor chemotherapy but has severe ototoxic side effects, including tinnitus and hearing damage. This study aimed to determine the molecular mechanism underlying cisplatin-induced ototoxicity. In this study, we used CBA/CaJ mice to establish an ototoxicity model of cisplatin-induced hair cell loss, and our results showed that cisplatin treatment could reduce FOXG1 expression and autophagy levels. Additionally, H3K9me2 levels increased in cochlear hair cells after cisplatin administration. Reduced FOXG1 expression caused decreased microRNA (miRNA) expression and autophagy levels, leading to reactive oxygen species (ROS) accumulation and cochlear hair cell death. Inhibiting miRNA expression decreased the autophagy levels of OC-1 cells and significantly increased cellular ROS levels and the apoptosis ratio in vitro. In vitro, overexpression of FOXG1 and its target miRNAs could rescue the cisplatin-induced decrease in autophagy, thereby reducing apoptosis. BIX01294 is an inhibitor of G9a, the enzyme in charge of H3K9me2, and can reduce hair cell damage and rescue the hearing loss caused by cisplatin in vivo. This study demonstrates that FOXG1-related epigenetics plays a role in cisplatin-induced ototoxicity through the autophagy pathway, providing new ideas and intervention targets for treating ototoxicity.

Keywords: FOXG1; autophagy; cisplatin; epigenetics; hair cells; ototoxicity.

Grants and funding

This work was financially supported by the National Natural Science Foundation of China (Nos. 81873700, 82222017, and 82271183), Hubei Province's Key Research and Development Program (No. 2022BCA046), the Fundamental Research Funds for the Central Universities (2042022kf0059), and the Knowledge Innovation Program of Wuhan-Shuguang (2022020801020493).