Interplay between Menin and K-Ras in Regulating Lung Adenocarcinoma |
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Authors: | Yuan Wu Zi-Jie Feng Shu-Bin Gao Smita Matkar Bin Xu Hong-Bin Duan Xiao Lin Shan-Hua Li Xianxin Hua Guang-Hui Jin |
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Institution: | From the ‡Department of Basic Medical Sciences, Medical College and ;the ‖Department of Thoracic Surgery, Zhongshan Hospital, Xiamen University, 361005 Fujian, China.;the §Department of Radiotherapy, Hubei Cancer Hospital, 430079 Hubei, China, and ;the ¶Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104 |
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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-RasG12D-induced tumor formation in the Men1f/f;K-RasG12D/+;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. |
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Keywords: | DNA Methylation DNA Methyltransferase Epigenetics Lung Cancer Ras DNA Methylation K-Ras MEN1 Menin |
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