MLL3 loss drives metastasis by promoting a hybrid epithelial–mesenchymal transition state

Jihong Cui, Chi Zhang, Ji Eun Lee, Boris A. Bartholdy, Dapeng Yang, Yu Liu, Piril Erler, Phillip M. Galbo, Dayle Q. Hodge, Danwei Huangfu, Deyou Zheng, Kai Ge, Wenjun Guo

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Phenotypic plasticity associated with the hybrid epithelial–mesenchymal transition (EMT) is crucial to metastatic seeding and outgrowth. However, the mechanisms governing the hybrid EMT state remain poorly defined. Here we showed that deletion of the epigenetic regulator MLL3, a tumour suppressor frequently altered in human cancer, promoted the acquisition of hybrid EMT in breast cancer cells. Distinct from other EMT regulators that mediate only unidirectional changes, MLL3 loss enhanced responses to stimuli inducing EMT and mesenchymal–epithelial transition in epithelial and mesenchymal cells, respectively. Consequently, MLL3 loss greatly increased metastasis by enhancing metastatic colonization. Mechanistically, MLL3 loss led to increased IFNγ signalling, which contributed to the induction of hybrid EMT cells and enhanced metastatic capacity. Furthermore, BET inhibition effectively suppressed the growth of MLL3-mutant primary tumours and metastases. These results uncovered MLL3 mutation as a key driver of hybrid EMT and metastasis in breast cancer that could be targeted therapeutically.

Original languageEnglish (US)
Pages (from-to)145-158
Number of pages14
JournalNature Cell Biology
Volume25
Issue number1
DOIs
StatePublished - Jan 2023

ASJC Scopus subject areas

  • Cell Biology

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