MLL3 Loss Drives Metastasis by Promoting a Hybrid Epithelial-Mesenchymal Transition State [ChIP-seq UTX and MLL4]

Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) state is crucial to metastatic seeding and outgrowth. However, the mechanisms controlling the induction of hybrid EMT remain poorly defined. We showed that deletion of the epigenetic regulator MLL3, a tumor suppressor frequently altered in human cancer, promoted the acquisition of the hybrid EMT state in both epithelial and mesenchymal breast cancer cells by facilitating EMT and MET, distinct from other known EMT regulators mediating unidirectional changes. Consequently, MLL3 deletion greatly increased metastasis by enhancing metastatic outgrowth during colonization. Mechanistically, MLL3 loss led to IFN? signaling upregulation, which contributes to the induction of hybrid EMT cells and the enhanced metastatic capacity. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for UTX and MLL4 in MLL3-WT and Mut MCF7 and MDA-MB-231 cells.