HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma Journal Article

   


Authors: Takeda, S.; Liu, H.; Sasagawa, S.; Dong, Y.; Trainor, P. A.; Cheng, E. H.; Hsieh, J. J.
Article Title: HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma
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.
Keywords: signal transduction; controlled study; unclassified drug; cancer growth; liver cell carcinoma; nonhuman; mouse; phenotype; animal tissue; animal experiment; animal model; protein interaction; cancer cell culture; scatter factor; transcription regulation; histone h3; cell migration; interstitial collagenase; myoblast; scatter factor receptor; stromelysin; mixed lineage leukemia protein; hypoglossal nerve disease; ets2 protein
Journal Title: Journal of Clinical Investigation
Volume: 123
Issue: 7
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2013-07-01
Start Page: 3154
End Page: 3165
Language: English
DOI: 10.1172/jci65566
PROVIDER: scopus
PMCID: PMC3696564
PUBMED: 23934123
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84879654614&partnerID=40&md5=d7aa113a7d93e79aea33bfda169b27a8
Notes: --- - Cited By (since 1996):1 - "Export Date: 1 August 2013" - "CODEN: JCINA" - "Source: Scopus"
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MSK Authors
  1. Yiyu Dong
    26 Dong
  2. Shugaku Takeda
    18 Takeda
  3. James J Hsieh
    125 Hsieh
  4. Han Liu
    13 Liu
  5. Emily H Cheng
    78 Cheng
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