1. Elucidation of the Hdac2/Sp1/miR-204-5p/Bcl-2 axis as a modulator of cochlear apoptosis via in vivo/in vitro models of acute hearing loss
- Author
-
Lisheng Xie, Jie Hou, Zhibiao Liu, Yanhong Dai, Qiongqiong Zhou, Wandong She, Xiaoping Du, Xiaorui Chen, and Bing Fei
- Subjects
0301 basic medicine ,Hearing loss ,Biology ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Drug Discovery ,medicine ,Transcriptional regulation ,otorhinolaryngologic diseases ,Hdac2 ,transcriptional regulation ,Cochlea ,Spiral ganglion ,Sp1 transcription factor ,Histone deacetylase 2 ,lcsh:RM1-950 ,apoptosis ,acute hearing loss ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Therapeutics. Pharmacology ,Apoptosis ,030220 oncology & carcinogenesis ,Molecular Medicine ,Original Article ,sense organs ,medicine.symptom - Abstract
We previously reported that dysregulation of histone deacetylase 2 (Hdac2) was associated with the prognosis of sudden sensorineural hearing loss. However, the underlying molecular mechanisms are poorly understood. In the present study, we developed an acute hearing loss animal model in guinea pigs by infusing lipopolysaccharides (LPS) into the cochlea and measured the expression of Hdac2 in the sensory epithelium. We observed that the level of Hdac2 was significantly decreased in the LPS-infused cochleae. The levels of apoptosis-inhibition genes Bcl-2 and Bcl-xl were also decreased in the cochlea and correlated positively with the levels of Hdac2. Caspase3 or TUNEL-positive spiral ganglion neurons, hair cells, and supporting cells were observed in the LPS-infused cochleae. These in vivo observations were recapitulated in cell culture experiments. Based on bioinformatics analysis, we found miR-204-5p was engaged in the regulation of Hdac2 on Bcl-2. Molecular mechanism experiments displayed that miR-204-5p could be regulated by Hdac2 through interacting with transcription factor Sp1. Taken together, these results indicated that the Hdac2/Sp1/miR-204-5p/Bcl-2 regulatory axis mediated apoptosis in the cochlea, providing potential insights into the progression of acute hearing loss. To our knowledge, the study describes a miRNA-related mechanism for Hdac2-mediated regulation in the cochlea for the first time., Graphical Abstract, Dysregulation of histone deacetylase 2 (Hdac2) was associated with the prognosis of sudden sensorineural hearing loss. However, the underlying molecular mechanisms are poorly understood. This study revealed a role of Hdac2/miR-204-5P/Bcl-2 axis in the apoptosis of cochlear cells and provided a potential insight into the pathogenesis of acute hearing loss.
- Published
- 2021