Interplay between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of the Hedgehog signaling pathway
Interplay between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of the Hedgehog signaling pathway
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menin 和 Dnmt1 之间的相互作用可逆地调节 Hedgehog 信号通路下游的胰腺癌细胞生长
DOI：
10.1016/j.canlet.2015.09.019
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发表时间：
2016-01-01
期刊：
影响因子：
9.7
通讯作者：
Hu, Xian-gui
中科院分区：
文献类型：
--
作者：
Cheng, Peng;Wang, Yun-feng;Hu, Xian-gui
Men 1基因的产物Menin在胰腺神经内分泌肿瘤中经常发生突变，其作为染色质重塑因子通过与组蛋白修饰因子相互作用来调节细胞周期调节因子的转录。然而，menin的功能及其在胰腺导管腺癌中的潜在机制仍不清楚。在这里，我们发现menin在体外和体内抑制胰腺癌细胞的生长，并且在胰腺癌发生过程中其表达逐渐丧失。Menin过表达显著激活了细胞周期蛋白依赖性激酶（CDK）抑制剂p18和p27的表达，并伴随着p18和p27启动子DNA甲基化水平的降低。从机制上讲，我们发现menin与DNA甲基转移酶1（Dnmt 1）的相互作用竞争性地将Dnmt 1从p18和p27启动子上拉下来，导致DNA甲基化水平下调。此外，menin的表达被Hedgehog信号通路下游的Dnmt 1抑制，并且menin过表达强烈拮抗Hedgehog信号通路对胰腺癌细胞增殖的促进作用。总之，menin和Dnmt 1之间的相互作用可逆地调节胰腺癌细胞生长下游的刺猬途径与复杂的相互调节网络，这表明刺猬/Dnmt 1/menin轴是胰腺癌治疗的潜在分子靶点。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Menin, the product of the Men1 gene, which is frequently mutated in pancreatic neuroendocrine tumors, acts as a chromatin-remodeling factor to modulate the transcription of cell cycle regulators by interacting with histone modification factors. However, the function of menin and its underlying mechanisms in pancreatic ductal adenocarcinoma remain unknown. Here, we found that menin inhibited pancreatic cancer cell growth in vitro and in vivo and that its expression was gradually lost during pancreatic carcinogenesis. Menin overexpression significantly activated the expression of the cyclin-dependent kinase (CDK) inhibitors p18 and p27, accompanied with a decrease in DNA methylation levels of p18 and p27 promoters. Mechanistically, we found that interaction of menin with DNA methyltransferase 1 (Dnmt1) competitively pulled down Dnmt1 from p18 and p27 promoters, leading to the downregulation of DNA methylation levels. Moreover, menin expression was suppressed by Dnmt1 downstream of the Hedgehog signaling pathway, and menin overexpression strongly antagonized the promotion effect of hedgehog signaling on pancreatic cancer cell proliferation. Taken together, the interaction between menin and Dnmt1 reversibly regulates pancreatic cancer cell growth downstream of Hedgehog pathways with complex mutual modulation networks, suggesting that the Hedgehog/Dnmt1/menin axis is a potential molecular target for pancreatic cancer therapy. (C) 2015 Elsevier Ireland Ltd. All rights reserved.