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 QOL functionally and cosmetically, with current treatment modalities unsatisfactory. Recent studies indicate that epi...

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Bibliographic Details
Published inJournal of investigative dermatology
Main Authors Almier, Nedaa, Leibowitz, Kassidy, Gower, Adam C., To, Samantha, Keller, Madelyn R., Connizzo, Brianne K., Roh, Daniel S., Alani, Rhoda M., Collard, Marianne
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 14.07.2024
Subjects
CoREST
Corin
Epigenetics
RNAseq
Scar
LSD1i
MMP
FDR
Scar
CoREST
Epigenetics
GSEA
RNAseq
HDACi
ECM
Corin
HDAC
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Summary:Keloids are pathological fibroproliferative scars resulting from abnormal collagen deposition within and beyond the margins of the initial cutaneous insult. Keloids negatively impact QOL functionally and cosmetically, with current treatment modalities unsatisfactory. Recent studies indicate that epigenetic dysregulation is central to the development and progression of keloids. In this study, we evaluate the functional significance of epigenetic targeting strategies in vitro using patient-derived keloid fibroblasts treated with small-molecule inhibitors of histone deacetylases, LSD1, CoREST, and p300, as potential therapies for keloids. We find that both the dual-acting CoREST inhibitor corin and the histone deacetylase inhibitor entinostat reduce fibroblast proliferation more than the LSD1 inhibitor GSK-LSD1; in addition, corin was the most effective inhibitor of migration and invasion across keloid fibroblasts. RNA-sequencing analysis of keloid fibroblasts treated with corin demonstrates coordinate upregulation of many genes, including key mediators of cell adhesion such as claudins. Corin also downregulates gene sets involved in cell cycle progression, including reduced expression of cyclins A1 and B2 compared with that of DMSO. These results highlight a significant role for epigenetic regulation of pathologic mediators of keloidal scarring and suggest that inhibitors of the epigenetic CoREST repressor complex may prove beneficial in the prevention and/or treatment of keloidal scarring in patients.
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ISSN:0022-202X
1523-1747
1523-1747
DOI:10.1016/j.jid.2024.06.1274