Department of Dermatology, Chobanian & Avedisian School of Medicine, Boston University, Boston, Massachusetts, USA.
Department of Dermatology, Chobanian & Avedisian School of Medicine, Boston University, Boston, Massachusetts, USA; The Tissue Repair and Regeneration Laboratory (TR2Lab), Faculty of Sciences and Technology, University of Vic - Central University of Catalonia, Vic, Spain.
J Invest Dermatol. 2024 Feb;144(2):378-386.e2. doi: 10.1016/j.jid.2023.07.022. Epub 2023 Aug 25.
Wound healing is a complex process involving phases of hemostasis, inflammation, proliferation, and remodeling. The regenerative process in the skin requires coordination between many regulators, including signaling molecules, transcription factors, and the epigenetic machinery. In this study, we show that chromatin regulators HDAC1 and LSD1, key components of the CoREST repressor complex, are upregulated in the regenerating epidermis during wound repair. We also show that corin, a synthetic dual inhibitor of the CoREST complex and HDAC1/LSD1 activities, significantly accelerates wound closure through enhanced re-epithelialization in a mouse tail wound model. Acetylated H3K9 (methylation of histone H3 at lysine 9) expression, a histone modification targeted by HDAC1, is increased in keratinocytes after topical treatment with 100 nM and 1 μM of corin. In vitro experiments demonstrate that corin promotes migration and inhibits the proliferation of human keratinocytes. Furthermore, expression levels of genes promoting keratinocyte migration, such as AREG, CD24, EPHB2, ITGAX, PTGS, SCT1, SERPINB2, SERPINE1, SLPI, SNAI2, and TWIST, increased in keratinocytes treated with corin. These data demonstrate that dual inhibition of class I histone deacetylases and LSD1 by corin may serve as a new approach for promoting wound re-epithelialization and provide a platform for further applications of corin for the treatment of chronic wounds.
伤口愈合是一个复杂的过程，涉及止血、炎症、增殖和重塑等阶段。皮肤的再生过程需要许多调节剂的协调，包括信号分子、转录因子和表观遗传机制。在这项研究中，我们表明，染色质调节剂 HDAC1 和 LSD1 是 CoREST 抑制复合物的关键组成部分，在伤口修复过程中再生表皮中上调。我们还表明，corin 是 CoREST 复合物和 HDAC1/LSD1 活性的合成双重抑制剂，通过增强小鼠尾巴伤口模型中的再上皮化，显著加速伤口闭合。用 100 nM 和 1 μM corin 处理角质细胞后，乙酰化 H3K9（组蛋白 H3 在赖氨酸 9 处的甲基化）表达增加，这是 HDAC1 靶向的一种组蛋白修饰。体外实验表明，corin 促进人角质细胞的迁移并抑制其增殖。此外，corin 处理的角质细胞中促进角质细胞迁移的基因的表达水平增加，例如 AREG、CD24、EPHB2、ITGAX、PTGS、SCT1、SERPINB2、SERPINE1、SLPI、SNAI2 和 TWIST。这些数据表明，corin 对 I 类组蛋白去乙酰酶和 LSD1 的双重抑制可能成为促进伤口再上皮化的新方法，并为 corin 治疗慢性伤口的进一步应用提供了一个平台。
