HDAC5-mediated Smad7 silencing through MEF2A is critical for fibroblast activation and hypertrophic scar formation

• Published in: International journal of biological sciences 2022-01, Vol.18 (15), p.5724-5739
• Main Authors: Gao, Ya, Liu, Yangdan, Zheng, Danning, Ho, Chiakang, Wen, Dongsheng, Sun, Jiaming, Huang, Lu, Liu, Yuxin, Li, Qingfeng, Zhang, Yifan
• Format: Article
• Language: English
• Subjects: Cicatrix, Hypertrophic - genetics; Cicatrix, Hypertrophic - metabolism; Depletion; Drug dosages; Ethics; Eutrophication; Experiments; Fibroblasts; Fibroblasts - metabolism; Fibrosis; Gene expression; Growth factors; Histone deacetylase; Histone Deacetylases - metabolism; Humans; Hyperplasia; Laboratory animals; Luciferases - metabolism; Medical research; MEF2 Transcription Factors - metabolism; Myocytes; Phosphorylation; Prophylaxis; Regulatory mechanisms (biology); Research Paper; Signaling; Smad2 protein; Smad7 protein; Smad7 Protein - metabolism; Sutures; Transforming Growth Factor beta - metabolism; Transforming growth factor-b1; Transforming Growth Factors - metabolism
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.76140

Transforming growth factor-β (TGF-β) signaling plays a key role in excessive fibrosis. As a class IIa family histone deacetylase (HDAC), HDAC5 shows a close relationship with TGF-β signaling and fibrosis. However, the effect and regulatory mechanism of HDAC5 in hypertrophic scar (HS) formation remain elusive. We show that HDAC5 was overexpressed in HS tissues and depletion of HDAC5 attenuated HS formation and inhibited fibroblast activation . HDAC5 knockdown (KD) significantly downregulated TGF-β1 induced Smad2/3 phosphorylation and increased Smad7 expression. Meanwhile, Smad7 KD rescued the Smad2/3 phosphorylation downregulation and scar hyperplasia inhibition mediated by HDAC5 deficiency. Luciferase reporter assays and ChIP-qPCR assays revealed that HDAC5 interacts with myocyte enhancer factor 2A (MEF2A) suppressing MEF2A binding to the Smad7 promoter region, which results in Smad7 promoter activity repression. HDAC4/5 inhibitor, LMK235, significantly alleviated hypertrophic scar formation. Our study provides clues for the development of HDAC5 targeting strategies for the therapy or prophylaxis of fibrotic diseases.