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

Lisheng Xie; Qiongqiong Zhou; Xiaorui Chen; Xiaoping Du; Zhibiao Liu; Bing Fei; Jie Hou; Yanhong Dai; Wandong She

doi:10.1016/j.omtn.2021.01.017

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

Mol Ther Nucleic Acids. 2021 Jan 20:23:1093-1109. doi: 10.1016/j.omtn.2021.01.017. eCollection 2021 Mar 5.

Authors

Lisheng Xie^{1

2}, Qiongqiong Zhou², Xiaorui Chen³, Xiaoping Du⁴, Zhibiao Liu¹, Bing Fei¹, Jie Hou¹, Yanhong Dai¹, Wandong She^{1

3}

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing 210008, China.
² Department of Otolaryngology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
³ Nanjing Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing 210008, China.
⁴ Hough Ear Institute, Oklahoma City, OK 73112, USA.

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.

Keywords: Hdac2; acute hearing loss; apoptosis; transcriptional regulation.