EMT is induced by the combination of TGF-β with other micro-environmental factors, and requires the activation of ZEB1 plus other target genes. Microenvironmental factors (Wnt, NF-kb agonists?) up-regulate Twist and Snail genes, which down-regulate GRHL2. This down-regulation alleviates the repression of the ZEB1 promoter, permitting TGF-β (partly, through Twist and Snail themselves) to activate ZEB1 expression. The down-regulation of GRHL2 also enhances Smad-mediated transactivation of TGF-β target genes, which, together with ZEB1, induce EMT and anoikis-resistance.