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

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 1

Mll–/– mice exhibit CNXII outgrowth and myoblast migration defects.

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Mll–/– mice exhibit CNXII outgrowth and myoblast migration defects. (...
(A) Lateral views of E10.5 embryos (somite #36) stained with the 2H3 anti-neurofilament Ab to visualize CNXII of WT, Mllnc/nc, and Tasp1–/– embryos (C57BL/6 background) or WT and Mll–/– embryos (CD1 background). Distance from the crossover of CNXII and CNX to the distal end of CNXII (arrowhead) was quantified and presented as mean ± SEM. *P < 0.05; **P < 0.01. Scale bars: 0.2 mm. (B) In situ hybridization on sections of E9.0 (somite #24) and E9.5 (somite #27) WT and Mll–/– embryos using a specific RNA probe against Pax3 mRNA was performed to visualize migratory myoblasts. Representative images of dermomyotomes at forelimbs are shown. Dashed outlines denote the exterior surface of the embryos at the forelimb bud level.