Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
J Clin Invest. 2013 Jul;123(7):3154-65. doi: 10.1172/JCI65566. Epub 2013 Jun 24.
HGF signals through its cognate receptor, MET, to orchestrate diverse biological processes, including cell proliferation, cell fate specification, organogenesis, and epithelial-mesenchymal transition. Mixed-lineage leukemia (MLL), an epigenetic regulator, plays critical roles in cell fate, stem cell, and cell cycle decisions. Here, we describe a role for MLL in the HGF-MET signaling pathway. We found a shared phenotype among Mll(-/-), Hgf(-/-), and Met(-/-) mice with common cranial nerve XII (CNXII) outgrowth and myoblast migration defects. Phenotypic analysis demonstrated that MLL was required for HGF-induced invasion and metastatic growth of hepatocellular carcinoma cell lines. HGF-MET signaling resulted in the accumulation of ETS2, which interacted with MLL to transactivate MMP1 and MMP3. ChIP assays demonstrated that activation of the HGF-MET pathway resulted in increased occupancy of the MLL-ETS2 complex on MMP1 and MMP3 promoters, where MLL trimethylated histone H3 lysine 4 (H3K4), activating transcription. Our results present an epigenetic link between MLL and the HGF-MET signaling pathway, which may suggest new strategies for therapeutic intervention.
HGF 通过其同源受体 MET 发出信号，以协调包括细胞增殖、细胞命运特化、器官发生和上皮-间充质转化在内的多种生物学过程。混合谱系白血病（MLL）是一种表观遗传调节剂，在细胞命运、干细胞和细胞周期决策中发挥关键作用。在这里，我们描述了 MLL 在 HGF-MET 信号通路中的作用。我们发现 Mll(-/-)、Hgf(-/-)和 Met(-/-) 小鼠之间存在共同的颅神经 XII（CNXII）生长和肌母细胞迁移缺陷的表型。表型分析表明，MLL 是 HGF 诱导的肝癌细胞系侵袭和转移生长所必需的。HGF-MET 信号导致 ETS2 的积累，其与 MLL 相互作用以反式激活 MMP1 和 MMP3。ChIP 测定表明，HGF-MET 途径的激活导致 MLL-ETS2 复合物在 MMP1 和 MMP3 启动子上的占有率增加，其中 MLL 三甲基化组蛋白 H3 赖氨酸 4（H3K4），激活转录。我们的结果在 MLL 和 HGF-MET 信号通路之间建立了一种表观遗传联系，这可能为治疗干预提供新的策略。
