| First Author | Takeda S | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 7 | Pages | 3154-65 |
| PubMed ID | 23934123 | Mgi Jnum | J:201612 |
| Mgi Id | MGI:5514463 | Doi | 10.1172/JCI65566 |
| Citation | Takeda S, et al. (2013) HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma. J Clin Invest 123(7):3154-65 |
| abstractText | 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. |
