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 Zeb1+/− mice, as Zeb1−/− 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. Zeb1+/− 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 ZEB+/− 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.

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Recent advancement in understanding cancer etiology has highlighted epigenetic deregulation as an important phenomenon leading to poor prognosis in glioblastoma (GBM). Polycomb repressive complex 2 (PRC2) is one such important epigenetic modifier reportedly altered in GBM. However, its defined mechanism in tumorigenesis still remains elusive. In present study, we analyzed our in‐house ChIPseq data for H3k27me3 modified miRNAs and identified miR‐490‐3p to be the most common target in GBM with significantly downregulated expression in glioma patients in both TCGA and GBM patient cohort. Our functional analysis delineates for the first time, a central role of PRC2 catalytic unit EZH2 in directly regulating expression of this miRNA and its host gene CHRM2 in GBM. In accordance, cell line treatment with EZH2 siRNA and 5‐azacytidine also confirmed its coregulation by CpG and histone methylation based epigenetic mechanisms. Furthermore, induced overexpression of miR‐490‐3p in GBM cell lines significantly inhibited key hallmarks including cellular proliferation, colony formation and spheroid formation, as well as epithelial‐to‐mesenchymal transition (EMT), with downregulation of multiple EMT transcription factors and promigratory genes (MMP9, CCL5, PIK3R1, ICAM1, ADAM17 and NOTCH1). We also for the first time report TGFBR1 and TGIF2 as two direct downstream effector targets of miR‐490‐3p that are also deregulated in GBM. TGIF2, a novel target, was shown to promote migration and EMT that could partially be rescued by miR‐490‐3p overexpression. Overall, this stands as a first study that provides a direct link between epigenetic modulator EZH2 and oncogenic TGF‐β signaling involving novel miR‐490‐3p/TGIF2/TGFBR1 axis, that being targetable might be promising in developing new therapeutic intervention strategies for GBM.