Abstract:
Epithelial to mesenchymal transition (EMT) and wound
vascularization are two critical interrelated processes that
enable cutaneous wound healing. Zinc finger E-box binding
homeobox 1 (ZEB1), primarily studied in the context of
tumor biology, is a potent EMT activator. ZEB1 is also
known to contribute to endothelial cell survival as well as
stimulate tumor angiogenesis. The role of ZEB1 in cutaneous wounds was assessed using Zeb11/2 mice, as Zeb12/2
mice are not viable. Quantitative stable isotope labeling
by amino acids in cell culture (SILAC) proteomics was used to
elucidate the effect of elevated ZEB1, as noted during hyperglycemia. Under different glycemic conditions, ZEB1 binding to E-cadherin promoter was investigated using chromatin
immunoprecipitation. Cutaneous wounding resulted in loss
of epithelial marker E-cadherin with concomitant gain of
ZEB1. The dominant proteins downregulated after ZEB1
overexpression functionally represented adherens junction
pathway. Zeb11/2 mice exhibited compromised wound closure complicated by defective EMT and poor wound angiogenesis. Under hyperglycemic conditions, ZEB1 lost its ability
to bind E-cadherin promoter. Keratinocyte E-cadherin, thus
upregulated, resisted EMT required for wound healing. Diabetic wound healing was improved in ZEB1/2 as well as in
db/db mice subjected to ZEB1 knockdown. This work recognizes ZEB1 as a key regulator of cutaneous wound healing
that is of particular relevance to diabetic wound complication
