Abstract
Menin is a scaffold protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene in humans, and it interacts with a variety of transcriptional proteins to control active or repressive cellular processes. Here, we show that heterozygous ablation of Men1 in female mice reduces chemical carcinogen-induced liver carcinogenesis and represses the activation of the inflammation pathway. Using ChIP-on-chip screens and ChIP assays, we find that menin occupancy frequently coincides with H3K4me3 at the promoter of many liver cancer-related genes, such as Yes-associated protein (Yap1). Increased menin and Yap1 expression in human hepatocellular carcinoma specimens was associated with poor prognosis. Our findings reveal that menin plays an important epigenetic role in promoting liver tumorigenesis, and support the notion that H3K4me3, which is regulated by the menin-mixed-lineage leukemia complex, is a potential therapeutic target in hepatocellular carcinoma.
Keywords:
H3K4 methylation; interleukin 6.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Carbon Tetrachloride / toxicity
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Carcinogenesis / chemically induced
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Carcinogenesis / genetics
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Carcinogenesis / metabolism
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Carcinoma, Hepatocellular / genetics*
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Carcinoma, Hepatocellular / metabolism
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Cell Cycle Proteins
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Cell Line, Tumor
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Chemical and Drug Induced Liver Injury / etiology
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Chemical and Drug Induced Liver Injury / genetics
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Chemical and Drug Induced Liver Injury / metabolism
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Chromatin Immunoprecipitation
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Diethylnitrosamine
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Epigenesis, Genetic
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Female
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Hep G2 Cells
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Humans
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Kaplan-Meier Estimate
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Liver Neoplasms / genetics*
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Liver Neoplasms / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Nude
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Oligonucleotide Array Sequence Analysis
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics*
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RNA Interference
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Up-Regulation
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Xenograft Model Antitumor Assays
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Men1 protein, mouse
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Phosphoproteins
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Proto-Oncogene Proteins
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YAP-Signaling Proteins
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Yap1 protein, mouse
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Diethylnitrosamine
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Carbon Tetrachloride