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HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma
Shugaku Takeda, … , Emily H. Cheng, James J. Hsieh
Shugaku Takeda, … , Emily H. Cheng, James J. Hsieh
Published June 24, 2013
Citation Information: J Clin Invest. 2013;123(7):3154-3165. https://doi.org/10.1172/JCI65566.
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Research Article

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

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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.

Authors

Shugaku Takeda, Han Liu, Satoru Sasagawa, Yiyu Dong, Paul A. Trainor, Emily H. Cheng, James J. Hsieh

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Figure 5

ETS2 protein accumulates upon HGF-MET signaling through blocked degradation and enhanced transcription.

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ETS2 protein accumulates upon HGF-MET signaling through blocked degradat...
(A) MLL protein remained constant upon HGF treatment. HepG2 cells were incubated with 20 ng/ml HGF for the indicated times and subjected to anti-MLLC180 IB analysis. (B) ETS2 protein accumulated upon HGF treatment. HepG2 cells treated with HGF for the indicated times without or with MG132 pretreatment (10 μM for 4 hours) were harvested and subjected to anti-ETS2 IB analysis. Numbers below lanes indicate relative protein levels of ETS2, measured by densitometry and normalized against nonspecific cross-reactive bands (asterisks). (C) ETS2 quantitative RT-PCR on HepG2 cells treated with HGF for the indicated times showed an induction peak at 2 hours. Data are mean ± SD from 3 independent experiments. (D) MLL knockdown had no effect on HGF-induced ETS2 accumulation. HepG2 cells transfected with the indicated siRNA oligos were treated with HGF for 3 hours and subjected to anti-ETS2 IB analysis. Asterisk denotes nonspecific cross-reactive band.

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