Abstract
MEN1, which encodes the nuclear protein menin, acts as a tumor suppressor in lung cancer and is often inactivated in human primary lung adenocarcinoma. Here, we show that the inactivation of MEN1 is associated with increased DNA methylation at the MEN1 promoter by K-Ras. On one hand, the activated K-Ras up-regulates the expression of DNA methyltransferases and enhances the binding of DNA methyltransferase 1 to the MEN1 promoter, leading to increased DNA methylation at the MEN1 gene in lung cancer cells; on the other hand, menin reduces the level of active Ras-GTP at least partly by preventing GRB2 and SOS1 from binding to Ras, without affecting the expression of GRB2 and SOS1. In human lung adenocarcinoma samples, we further demonstrate that reduced menin expression is associated with the enhanced expression of Ras (p < 0.05). Finally, excision of the Men1 gene markedly accelerates the K-Ras(G12D)-induced tumor formation in the Men1(f/f);K-Ras(G12D/+);Cre ER mouse model. Together, these findings uncover a previously unknown link between activated K-Ras and menin, an important interplay governing tumor activation and suppression in the development of lung cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism*
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Adenocarcinoma / pathology
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Animals
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Cell Line, Tumor
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methylation / genetics
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DNA, Neoplasm / genetics
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DNA, Neoplasm / metabolism
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GRB2 Adaptor Protein / genetics
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GRB2 Adaptor Protein / metabolism
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Gene Expression Regulation, Neoplastic*
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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Mice
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Mice, Mutant Strains
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Oncogene Protein p21(ras) / genetics
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Oncogene Protein p21(ras) / metabolism*
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins / biosynthesis*
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Proto-Oncogene Proteins / genetics
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SOS1 Protein / genetics
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SOS1 Protein / metabolism
Substances
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DNA, Neoplasm
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GRB2 Adaptor Protein
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GRB2 protein, human
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Grb2 protein, mouse
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MEN1 protein, human
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Men1 protein, mouse
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Proto-Oncogene Proteins
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SOS1 Protein
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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Oncogene Protein p21(ras)