Palmitoyl-KVK-L-ascorbic acid improves matrix abnormality associated with skin aging via inhibition of DNA methyltransferase 1

DNA methyltransferase 1 (DNMT1) is the most abundant DNA methyltransferase responsible for the maintenance of and also de novo DNA methylation. Here we investigated the effects of palmitoyl-KVK-L-ascorbic acid (VCC2,Duo-VitapepTM), a vitamin C-conjugated peptide with a potent DNMT1 inhibitory activity,on the expression of type I collagen and matrix metalloproteinase (MMP)-1 in vitro and in vivo. VCC2 showed a significant reduction of DNMT1 expression in UV-irradiated human dermal fibroblasts. Moreover, treatment of VCC2 or knockdown of DNMT1 significantly reversed matrix derangements associated with skin aging. Mechanistically, VCC2 could ameliorate the increased MMP-1-luc promoter activity induced by DNMT1 overexpression. Next, we examined whether VCC2 improved the matrix abnormalities found in intrinsically aged human skin in vivo. Indeed, topical application of VCC2 for 5 days led to increased type I procollagen expression and decreased MMP-1 expression in buttock skin from six elderly subjects. Collectively, our findings suggest that topical application of VCC2 may improve the matrix abnormalities and phenotypes associated with aged skin via DNMT1 regulation, suggesting that targeting epigenetic modifications may be an effective therapeutic modality against skin aging.