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

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

doi:10.1172/jci65566

Cited by 55 publications

(38 citation statements)

References 54 publications

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“…MLL, an epigenetic regulator, plays a critical role in acute leukemias, but the putative biological function of MLL in the liver is not well defined. Supporting our notion, HGF-MET (hepatocyte growth factor-mesenchymal epithelial transition factor) signals were reported to promote the expression of matrix metallopeptidases (MMPs), and the development of HCC through the ETS2-MLL complex mediated H3K4me3 (23). Strikingly, whole-genome sequencing analysis revealed that the MLL family of methyltransferases for H3K4 was somatically mutated in HCCs (24), which further supports the biological relevance of MLL in HCC.…”

Section: Discussionmentioning

confidence: 53%

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription

Zheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Epigenetic changes commonly occur in hepatocellular carcinoma (HCC) and are associated with aberrant gene expression. Most studies have focused on epigenetic gene-silencing events; therefore, the mechanism that promotes gene activation in HCC is not well established. We identify an epigenetic activation mechanism whereby menin promotes Yes-associated protein (Yap1) transcription, which is associated with a poor prognosis for HCC patients. Substantial overexpression of the menin–mixed-lineage leukemia complex is associated with increased histone 3 lysine 4 trimethylation at certain loci of the tumor promoter in HCC. Heterozygous ablation of multiple endocrine neoplasia type 1 ( Men1) in mice reduces diethylnitrosamine-induced development of HCC. Our findings reveal that menin plays an important epigenetic role in up-regulating Yap1 transcription, leading to liver tumorigenesis.

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Section: Discussionmentioning

confidence: 53%

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription

Zheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…7,116 KMT2A has also been shown to be a key downstream effector of the hepatocyte growth factor (HGF)–MET signaling pathway and facilitates metastasis in a hepatocellular carcinoma model. 117 The essential functions of wild type KMT2A have also been demonstrated in KMT2A-rearranged MLL (see Box 2). 118 Specifically, knockdown of KMT2A by shRNA, or genetic deletion of wild type KMT2A leads to decreased growth of MLL-AF9 transformed cells and the mice receiving KMT2A depleted cells do not succumb to leukemia.…”

Section: Kmt2 Mutations Span a Diverse Set Of Human Cancersmentioning

confidence: 99%

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

2015

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Preface Lysine methyltransferase 2 family (KMT2) proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thus impart critical functions through modulating chromatin structures and DNA accessibility. While the human KMT2 family was initially named the mixed lineage leukemia (MLL) family, due to the role of the founding member KMT2A (also called MLL, MLL1, ALL-1, HRX) in this disease, recent exome-sequencing studies revealed KMT2 genes to be among the most frequently mutated genes in many types of human cancers. Efforts to integrate the molecular mechanisms of KMT2 with its roles in tumorigenesis have led to the development of first-generation inhibitors of KMT2 function, which could become novel cancer therapies.

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“…MLL functions as heterodimeric complexes composed of its amino (MLL N320 ) and carboxy (MLL C180 ) terminal segments following site-specific proteolysis of its full-length precursor polypeptide by the Taspase1 protease (Hsieh et al, 2003; Oyama et al, 2013; Takeda et al, 2006; Takeda et al, 2013). Additional regulation of MLL function involves its biphasic accumulation and proteasome-mediated degradation coinciding with the cell cycle, coordinated by the ubiquitin-proteasome system E3 SCF Skp2 and APC Cdc20 at S and M phases, respectively (Liu et al, 2007; Liu et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Proteasome Inhibitors Evoke Latent Tumor Suppression Programs in Pro-B MLL Leukemias through MLL-AF4

et al. 2014

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SUMMARY Chromosomal translocations disrupting MLL generate MLL-fusion proteins that induce aggressive leukemias. Unexpectedly, MLL-fusion proteins are rarely observed at high levels, suggesting excessive MLL-fusions may be incompatible with a malignant phenotype. Here, we used clinical proteasome inhibitors, bortezomib and carfilzomib, to reduce the turnover of endogenous MLL-fusions and discovered that accumulated MLL-fusions induce latent, context-dependent tumor suppression programs. Specifically, in MLL pro-B lymphoid, but not myeloid, leukemias, proteasome inhibition triggers apoptosis and cell cycle arrest involving activation cleavage of BID by Caspase-8 and upregulation of p27, respectively. Furthermore, proteasome inhibition conferred preliminary benefit to MLL-AF4 leukemia patients. Hence, feasible strategies to treat cancer-type and oncogene specific cancers can be improvised through harnessing inherent tumor suppression properties of individual oncogenic fusions.

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

Cited by 55 publications

References 54 publications

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription

Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

Proteasome Inhibitors Evoke Latent Tumor Suppression Programs in Pro-B MLL Leukemias through MLL-AF4

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