HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • June 24, 2013

Research

keywords

  • Carcinoma, Hepatocellular
  • Hepatocyte Growth Factor
  • Liver Neoplasms, Experimental
  • Myeloid-Lymphoid Leukemia Protein
  • Proto-Oncogene Protein c-ets-2
  • Proto-Oncogene Proteins c-met

Identity

PubMed Central ID

  • PMC3696564

Scopus Document Identifier

  • 84879654614

Digital Object Identifier (DOI)

  • 10.1016/j.jneumeth.2005.12.021

PubMed ID

  • 23934123

Additional Document Info

volume

  • 123

issue

  • 7