VE-cadherin promotes vasculogenic mimicry by modulating kaiso-dependent gene expression

Aberrant extra-vascular expression of VE-cadherin (VEC) has been observed in metastasis associated with Vasculogenic Mimicry (VM), however the ultimate reason why nonendothelial VEC favors the acquisition of this phenotype is not established. In this study, we show that human malignant melanoma cells have a constitutively high expression of phoshoVEC(pVEC) at Y658; pVEC is a target of Focal Adhesion Kinase (FAK) and form a complex with p120-catenin and the transcriptional repressor kaiso in the nucleus. FAK inhibition enabled kaiso to suppress expression of its target genes and enhanced kaiso recruitment to KBS-containing promoters. Finally we have found that ablation of kaisorepressed genes WNT11 and CCDN1 abolished VM. Thus, identification of pVEC as a component of the kaiso transcriptional complex establishes a molecular paradigm that links FAK-dependent phosphorylation of VEC as a major mechanism by which ectopical VEC expression exerts its function in vasculogenic mimicry.