Department of Basic Medical Sciences, Medical College, Zhongshan Hospital, Xiamen University, 361005 Fujian, China.
J Biol Chem. 2012 Nov 16;287(47):40003-11. doi: 10.1074/jbc.M112.382416. Epub 2012 Oct 1.
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.
MEN1 编码核蛋白 menin，作为肺癌的肿瘤抑制因子，在人类原发性肺腺癌中常失活。在这里，我们表明 MEN1 的失活与 K-Ras 引起的 MEN1 启动子处的 DNA 甲基化增加有关。一方面，激活的 K-Ras 上调 DNA 甲基转移酶的表达，并增强 DNA 甲基转移酶 1 与 MEN1 启动子的结合，导致肺癌细胞中 MEN1 基因的 DNA 甲基化增加；另一方面，menin 通过防止 GRB2 和 SOS1 与 Ras 结合，至少部分地降低活性 Ras-GTP 的水平，而不影响 GRB2 和 SOS1 的表达。在人类肺腺癌样本中，我们进一步证明，menin 表达的降低与 Ras 的表达增强有关（p<0.05）。最后，切除 Men1 基因可显著加速 Men1(f/f)；K-Ras(G12D)/+；Cre ER 小鼠模型中 K-Ras(G12D)诱导的肿瘤形成。总之，这些发现揭示了激活的 K-Ras 和 menin 之间以前未知的联系，这是调节肺癌发生过程中肿瘤激活和抑制的重要相互作用。
