Epigenetic Control of the Invasion-promoting MT1-MMP/MMP-2/TIMP-2 Axis in Cancer Cells
Epigenetic Control of the Invasion-promoting MT1-MMP/MMP-2/TIMP-2 Axis in Cancer Cells
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DOI：
10.1074/jbc.m900273200
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发表时间：
2009-05-08
影响因子：
4.8
通讯作者：
Strongin, Alex Y.
中科院分区：
文献类型：
--
作者：
Chernov, Andrei V.;Sounni, Nor Eddine;Strongin, Alex Y.
1 型膜基质金属蛋白酶 (MT1-MMP) 是可溶性 MMP-2 的激活剂。两种 MMP 的活性均受其生理抑制剂 TIMP-2 调节。 MT1-MMP/MMP-2/TIMP-2 轴在许多细胞类型的侵袭行为中发挥着关键作用。尽管其重要性，但对该促侵袭轴的表观遗传控制研究还不够充分，因此，以合理且临床有益的方式对其进行修改极其困难。因此，我们对高度迁移的胶质母细胞瘤细胞和低度迁移的乳腺癌MCF-7细胞中的MT1-MMP、MMP-2和TIMP-2基因启动子进行了表观遗传学分析。我们首次确定导致两种 MMP 转录沉默的表观遗传控制包括相应 CpG 区域的超甲基化和组蛋白 H3 赖氨酸 27 三甲基化 (H3K27me3)。反过来，CpG 岛甲基化不足和组蛋白 H3 赖氨酸 27 三甲基化水平低是侵袭性癌细胞中转录活性 MT1-MMP 和 MMP-2 基因的特征。我们分析的其他组蛋白修饰（包括 H3ac 和 H3K4me2）存在于两种 MMP 的转录活性和非活性启动子中。组蛋白 H3 赖氨酸 4 三甲基化可能在调节 MT1-MMP 和 MMP-2 中不起重要作用。 TIMP-2 的表观遗传调控模式与 MMP 明显不同，包括启动子中两个 CpG 区域的协调甲基化和去甲基化。我们的结果表明，表观遗传控制在 MT1-MMP/MMP-2/TIMP-2 轴的平衡调节和癌细胞的侵袭行为中发挥着重要作用。
Membrane type-1 matrix metalloproteinase (MT1-MMP) is an activator of soluble MMP-2. The activity of both MMPs is regulated by their physiological inhibitor TIMP-2. An MT1-MMP/MMP-2/TIMP-2 axis plays a key role in the invasive behavior of many cell types. Despite its importance, epigenetic control of this pro-invasive axis is insufficiently studied, and, as a result, its modification in a rational and clinically beneficial manner is exceedingly difficult. Therefore, we performed an epigenetic analysis of the MT1-MMP, MMP-2, and TIMP-2 gene promoters in highly migratory glioblastoma cells and in low migratory breast carcinoma MCF-7 cells. We determined, for the first time, that the epigenetic control leading to the transcriptional silencing of both MMPs includes hypermethylation of the corresponding CpG regions and histone H3 lysine-27 trimethylation (H3K27me3). In turn, undermethylation of the CpG islands and low levels of histone H3 lysine-27 trimethylation are features of transcriptionally active MT1-MMP and MMP-2 genes in invasive cancer cells. Additional histone modifications we have analyzed, including H3ac and H3K4me2, are present in both transcriptionally active and inactive promoters of both MMPs. Histone H3 lysine-4 trimethylation is likely to play no significant role in regulating MT1-MMP and MMP-2. The pattern of epigenetic regulation of TIMP-2 was clearly distinct from that of MMPs and included the coordinated methylation and demethylation of the two CpG regions in the promoter. Our results suggest that the epigenetic control plays an important role in both the balanced regulation of the MT1-MMP/MMP-2/TIMP-2 axis and the invasive behavior in cancer cells.