Adiponectin ameliorates hypertrophic scar by inhibiting Yes-associated protein transcription through SIRT1-mediated deacetylation of C/EBPβ and histone H3

Jian Zhang; Yan Li; Jiaqi Liu; Fu Han; Jihong Shi; Gaofeng Wu; Kejia Wang; Kuo Shen; Ming Zhao; Xiaowen Gao; Chenyang Tian; Yunchuan Wang; Ke Tao; Dahai Hu

doi:10.1016/j.isci.2022.105236

Adiponectin ameliorates hypertrophic scar by inhibiting Yes-associated protein transcription through SIRT1-mediated deacetylation of C/EBPβ and histone H3

iScience. 2022 Sep 28;25(10):105236. doi: 10.1016/j.isci.2022.105236. eCollection 2022 Oct 21.

Authors

Jian Zhang¹, Yan Li¹, Jiaqi Liu¹, Fu Han¹, Jihong Shi¹, Gaofeng Wu², Kejia Wang¹, Kuo Shen¹, Ming Zhao¹, Xiaowen Gao¹, Chenyang Tian¹, Yunchuan Wang¹, Ke Tao¹, Dahai Hu¹

Affiliations

¹ Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
² The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, P.R. China.

Abstract

The clinical correlation between adiponectin (APN) signal and hypertrophic scar (HS) remains unclear. Here, we found significantly reduced expression of APN receptors (AdipoR1/2) in HS tissues and derived fibroblasts (HFs), suggesting that HS formation may be associated with APN/AdipoR1/2 decline. RNA sequencing and RT-PCR validation revealed that APN significantly elevated the expression of SIRT1. Both in vitro and in vivo experiments confirmed that SIRT1 plays important role in APN inhibiting the fibrotic phenotype transformation and proliferation of scar fibroblasts and improving skin fibrosis. Mechanistically, SIRT1 inhibited the acetylation of C/EBPβ K39, histone H3K27, and H3K9, resulting in impaired transcription activity of C/EBPβ and compact chromatin conformation, thus preventing C/EBPβ from activating the transcription of YAP. Moreover, we found that YAP was critical for the transcriptional regulation of CTGF, CCND1, and CCNE1 by TEAD4. In conclusion, our study revealed the role of APN in antagonizing HS fibrosis by regulating the SIRT1/C/EBPβ/YAP pathway.

Keywords: Biological sciences; molecular biology; molecular mechanism of gene regulation.