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 IFNγ signaling upregulation, which contributes to the induction of hybrid EMT cells and the enhanced metastatic capacity. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for UTX and MLL4 in MLL3-WT and Mut MCF7 and MDA-MB-231 cells.

与混合上皮间质转化（epithelial-mesenchymal transition, EMT）状态相关的表型可塑性，对于肿瘤转移定植与增殖具有关键作用。然而，调控混合EMT状态诱导的分子机制迄今仍未得到充分阐明。本研究证实，表观遗传调控因子MLL3——一种在人类癌症中频发突变的肿瘤抑制基因——可通过促进上皮间质转化（EMT）与间质上皮转化（mesenchymal-epithelial transition, MET），在上皮型及间质型乳腺癌细胞中诱导获得混合EMT状态，这一调控模式与其他已知介导单向表型转化的EMT调控因子截然不同。因此，MLL3缺失可通过增强定植阶段的转移增殖能力，显著提升肿瘤转移潜能。机制层面分析显示，MLL3缺失会导致干扰素γ（IFNγ）信号通路上调，该通路活化可促进混合EMT细胞的诱导并增强肿瘤转移能力。本研究针对MLL3野生型（MLL3-WT）与突变型（MLL3-Mut）的MCF7及MDA-MB-231细胞，开展了UTX与MLL4的染色质免疫沉淀测序（chromatin immunoprecipitation DNA-sequencing, ChIP-seq）实验。