HGF-MET signals via the MLL-ETS2 complex in hepatocellular carcinoma
Shugaku Takeda, Han Liu, Satoru Sasagawa, Yiyu Dong, Paul A. Trainor, Emily H. Cheng, James J. Hsieh
Shugaku Takeda, Han Liu, Satoru Sasagawa, Yiyu Dong, Paul A. Trainor, Emily H. Cheng, James J. Hsieh
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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 7

MLL silencing severely compromised metastatic growth of HepG2 cells.

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MLL silencing severely compromised metastatic growth of HepG2 cells. (A)...
(A) MLL was stably knocked down in HepG2 cells by retrovirus carrying MLL shRNA in HepG2 cells (right). NSG mice were xenografted with HepG2 cells by tail vein injection. Representative images of livers harvested at necropsy and BLI of xenografted mice are shown (left). Color scale depicts photon flux. shScr, scrambled shRNA control. (B) Proposed model by which active HGF-MET signals lead to increased occupancy of the MLL-ETS2 complex on MMP1 and MMP3 promoters, where MLL induces H3K4me3, thereby activating target gene expression.