Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Int J Biol Sci. 2022 Sep 11;18(15):5724-5739. doi: 10.7150/ijbs.76140. eCollection 2022.
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.
转化生长因子-β（TGF-β）信号通路在过度纤维化中起着关键作用。组蛋白去乙酰化酶（HDAC）5 作为 IIa 类家族成员，与 TGF-β信号通路和纤维化密切相关。然而，HDAC5 在肥厚性瘢痕（HS）形成中的作用和调控机制仍不清楚。我们发现 HDAC5 在 HS 组织中过度表达，敲低 HDAC5 可减轻 HS 形成并抑制成纤维细胞激活。HDAC5 敲低（KD）显著下调 TGF-β1 诱导的 Smad2/3 磷酸化，并增加 Smad7 表达。同时，Smad7 KD 挽救了由 HDAC5 缺乏介导的 Smad2/3 磷酸化下调和瘢痕增生抑制。荧光素酶报告基因检测和 ChIP-qPCR 检测表明，HDAC5 与肌细胞增强因子 2A（MEF2A）相互作用，抑制 MEF2A 与 Smad7 启动子区域结合，从而抑制 Smad7 启动子活性。HDAC4/5 抑制剂 LMK235 显著减轻了肥厚性瘢痕的形成。我们的研究为开发针对 HDAC5 的靶向治疗策略提供了线索，以预防和治疗纤维化疾病。
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