Targeting the Epigenome Reduces Keloid Fibroblast Cell Proliferation, Migration and Invasion
Keloids are pathological fibroproliferative scars resulting from abnormal collagen deposition within and beyond the margins of the initial cutaneous insult. Keloids negatively impact quality of life cosmetically and functionally and have unsatisfactory treatment modalities with adverse side effects and high reoccurrence rates. Recent studies indicate that epigenetic dysregulation is involved in the development and progression of keloids, suggesting that this could be a viable therapeutic target. The purpose of this study was to evaluate epigenetic targeting drugs, HDACi, LSD1i, Corin, and A-485, as potential therapies for keloids using in-vitro model systems with patient-derived keloid fibroblasts. Results demonstrated that both dual-acting CoREST inhibitor, corin, and HDAC inhibitor, MS-275, reduced fibroblast proliferation more than the LSD1 inhibitor. Corin was the most effective inhibitor of keloid fibroblast migration and invasion across keloid cell lines and primary cells. RNA-seq analysis showed that corin treatment upregulated a significant number of genes with an enrichment in neural differentiation and cell adhesion gene sets. Specifically, corin increased the expression of claudins, which may cause increased cell adhesion and contribute to corin-induced reductions in migration and invasion. Corin downregulated gene sets involved in cell cycle progression, confirmed by reductions in Cyclin A1 and Cyclin B2 at the protein level compared to DMSO. These results highlight the significant role for epigenetic regulation in pathogenic keloid fibroblasts properties and indicate that the epigenetic inhibitor corin may be useful in the prevention and/or treatment of keloids. Overall design: Gene expression profiling analysis of RNA-seq data for patient keloid cells 1, 2, 3 & 4 (PK1, PK2, PK3, PK4) and patient normal fibroblasts 4 (PNF4) and how epigenetic drug (Corin) affects these cells compared to DMSO.