Abstract
Decreased expression of metallothionein-1 (MT-1) is associated with a poor prognosis in hepatocellular carcinoma (HCC). Here, we found that MT-1 expression was suppressed by 14-3-3ε, and MT-1 overexpression abolished 14-3-3ε-induced cell proliferation and tumor growth. We identified that 14-3-3ε induced expression of ZNF479, a novel potential transcriptional regulator by gene expression profiling and ZNF479 contributed to 14-3-3ε-suppressed MT-1 expression. ZNF479 induced the expression of DNMT1, UHRF1, and mixed-lineage leukemia (MLL) complex proteins (ASH2L and Menin), and increased tri-methylated histone H3 (H3K4me3) levels, but suppressed H3K4 (H3K4me2) di-methylation. ZNF479-suppressed MT-1 expression was restored by silencing of ASH2L and DNMT1. Furthermore, ZNF479 expression was higher in HCC tissues than that in the non-cancerous tissues. Expression analyses revealed a positive correlation between the expression of ZNF479 and DNMT1, UHRF1, ASH2L, and Menin, and an inverse correlation with that of ZNF479, ASH2L, Menin, and MT-1 isoforms. Moreover, correlations between the expression of ZNF479 and its downstream factors were more pronounced in HCC patients with hepatitis B. Here, we found that ZNF479 regulates MT-1 expression by modulating ASH2L in HCC. Approaches that target ZNF479/MLL complex/MT-1 or related epigenetic regulatory factors are potential therapeutic strategies for HCC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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14-3-3 Proteins / genetics
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14-3-3 Proteins / metabolism
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Animals
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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DNA (Cytosine-5-)-Methyltransferase 1 / genetics
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DNA (Cytosine-5-)-Methyltransferase 1 / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Elafin / antagonists & inhibitors
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Elafin / genetics
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Elafin / metabolism
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Hep G2 Cells
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Histones / metabolism
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Humans
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism*
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Liver Neoplasms / pathology
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / genetics
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Metallothionein / genetics
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Metallothionein / metabolism*
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Methylation
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transplantation, Heterologous
Substances
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14-3-3 Proteins
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ASH2L protein, human
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DNA-Binding Proteins
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Elafin
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Histones
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Nuclear Proteins
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PI3 protein, human
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Transcription Factors
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YWHAE protein, human
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ZNF479 protein, human
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histone H3 trimethyl Lys4
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metallothionein isoform 1
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Metallothionein
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DNA (Cytosine-5-)-Methyltransferase 1
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DNMT1 protein, human
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MTOR protein, human
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TOR Serine-Threonine Kinases