Reepithelialization of Diabetic Skin and Mucosal Wounds Is Rescued by Treatment With Epigenetic Inhibitors.

Abstract

FOXO1 expression in keratinocytes is needed for normal wound healing. In contrast, FOXO1 expression interferes with the closure of diabetic wounds. Using matrix metallopeptidase 9 as a model system, we found that high glucose significantly increased FOXO1-matrix metallopeptidase 9 interactions via increased DNA demethylation, reduced DNA methylation, and increased permissive histone-3 methylation invitro. Inhibitors of DNA demethylation and permissive histone-3 methylation improved the migration of keratinocytes exposed to high glucose invitro and the closure of diabetic skin and mucosal wounds invivo. Inhibition of epigenetic enzymes that alter FOXO1-induced gene expression dramatically improves diabetic healing and may apply to other conditions where FOXO1 has a detrimental role in diabetic complications.