HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma.
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.
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Shugaku
S
Takeda
Han
H
Liu
Satoru
S
Sasagawa
Yiyu
Y
Dong
Paul A
PA
Trainor
Emily H
EH
Cheng
James J
JJ
Hsieh
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000556:secondary; D004622:Embryo, Mammalian / Q000002:abnormalities; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D050787:Proto-Oncogene Protein c-ets-2 / Q000737:chemistry / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
C494069:ETS2 protein, human; D006657:Histones; C497422:KMT2A protein, human; D050787:Proto-Oncogene Protein c-ets-2; D051788:Myeloid-Lymphoid Leukemia Protein; D017228:Hepatocyte Growth Factor; D011495:Histone-Lysine N-Methyltransferase; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D053505:Matrix Metalloproteinases, Secreted