Suppression of lung adenocarcinoma through menin and polycomb gene-mediated repression of growth factor pleiotrophin.
Suppression of lung adenocarcinoma through menin and polycomb gene-mediated repression of growth factor pleiotrophin.
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通过 menin 和多梳基因介导的生长因子多效蛋白抑制抑制肺腺癌
DOI：
10.1038/onc.2009.273
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发表时间：
2009-11-19
期刊：
影响因子：
8
通讯作者：
Jin GH
中科院分区：
文献类型：
--
作者：
Gao SB;Feng ZJ;Xu B;Wu Y;Yin P;Yang Y;Hua X;Jin GH
Menin 上调细胞周期抑制剂的转录以抑制内分泌肿瘤，但人们对 menin 如何抑制非内分泌肿瘤（例如肺癌）知之甚少。在这里，我们证明 menin 抑制人肺癌细胞的增殖和小鼠肺癌的生长。 menin 介导的肿瘤抑制需要抑制生长因子多效蛋白 (PTN)，PTN 与其细胞表面受体、在某些肺腺癌中被激活的间变性淋巴瘤激酶 (ALK) 结合。 Menin 抑制 PTN 转录和 PTN 诱导的人肺癌细胞增殖，并且在原发性人肺腺癌中 menin 表达显着降低。值得注意的是，menin 结合 PTN 位点并增强 Polycomb 基因增强子 Zeste 同源物 2 (EZH2) 介导的组蛋白 H3 赖氨酸 27 三甲基化 (H3K27m3)，这是基因转录的负标记，但不影响内分泌细胞中的 menin 上调的组蛋白 H3K4 甲基化。总之，我们的研究结果表明，menin 部分通过增加 Polycomb 基因介导的 H3K27 甲基化和抑制 PTN 转录来抑制肺癌，揭示了一种新型的、表观遗传调节的 PTN-ALK 信号通路在抑制肺癌方面的作用。
Menin upregulates transcription of cell-cycle inhibitors to suppress endocrine tumors, but it is poorly understood how menin suppresses non-endocrine tumors such as lung cancer. Here, we show that menin inhibits proliferation of human lung cancer cells and growth of lung cancer in mice. The menin-mediated tumor suppression requires repression of growth factor pleiotrophin (PTN), which binds to its cell surface receptor, anaplastic lymphoma kinase (ALK) that is activated in certain lung adenocarcinomas. Menin represses PTN transcription and PTN-induced proliferation of human lung cancer cells, and menin expression is substantially reduced in primary human lung adenocarcinomas. Notably, menin binds the PTN locus and enhances Polycomb gene Enhancer of Zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27m3), a negative mark for gene transcription but does not affect histone H3K4 methylation that is usually upregulated by menin in endocrine cells. Together, our findings indicate that menin suppresses lung cancer partly through increasing Polycomb gene-mediated H3K27 methylation and repressing PTN transcription, unraveling a novel, epigenetically regulated PTN–ALK signaling pathway in suppressing lung cancer.