LAUSR

HighlightsGRHL2 is a master programmer of the epithelial phenotype that sensitized cells to NK killing at the level of NK‐target cell synaptogenesis.Sensitization was mediated by the up‐regulation of ICAM‐1.GRHL2‐KMT2C/D interactions and p300 inhibition were important for MET, ICAM‐1 up‐regulation and NK‐sensitization effects.ICAM‐1 expression correlated significantly with GRHL2 expression in lung tumors. Abstract Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead‐like‐2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down‐regulated during experimentally induced Epithelial‐Mesenchymal Transition (EMT). Here, we utilize GRHL2 re‐expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK‐sensitivity. GRHL2 enhanced the expression of ICAM‐1, augmenting NK‐target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti‐correlated with EMT. We identified two novel GRHL2‐interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal‐epithelial transition, NK‐sensitization and ICAM‐1 expression were promoted by GRHL2‐KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.