EZH2 regulates cofilin activity and colon cancer cell migration by targeting ITGA2 gene.
EZH2 regulates cofilin activity and colon cancer cell migration by targeting ITGA2 gene.
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DOI：
10.1371/journal.pone.0115276
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Pintzas A
中科院分区：
文献类型：
--
作者：
Ferraro A;Boni T;Pintzas A
通过肌动蛋白重塑来重组细胞骨架是细胞运动的基本步骤。虽然正常细胞和癌细胞的细胞迁移可以受到多种细胞内和细胞外因素的刺激，但所有路径最终都取决于丝切蛋白活性的调节。 Cofilin 是一种小型肌动蛋白结合蛋白，能够结合两种形式的肌动蛋白（球状和丝状），并受到丝氨酸 3 磷酸化的调节。丝氨酸 3 磷酸化后，肌动蛋白丝切蛋白失去活性，因此无法结合肌动蛋白分子，细胞骨架重塑受到损害。组蛋白甲基转移酶 EZH2 在包括结直肠癌 (CRC) 在内的许多肿瘤类型中经常过度表达。 EZH2 过度活性会导致表观遗传基因沉默，与许多肿瘤特性相关，包括侵袭、血管生成和转移，但人们对其背后的分子机制知之甚少。在此，我们报告 EZH2 能够通过涉及整合素信号传导的非传统新轴控制肌动蛋白丝切蛋白活性，从而控制 CRC 细胞系的细胞运动。事实上，我们展示了 EZH2 功能的遗传和药理学抑制（DZNep 和 GSK343）如何产生丝切蛋白的过度磷酸化并减少细胞迁移。我们之前通过染色质免疫沉淀证明整合素 α 2 (ITGα2) 表达受 EZH2 调节。在本研究中，我们提供的证据表明，在 EZH2 沉默的细胞中，去抑制的 ITGα2 的信号传导活性能够增加丝动蛋白磷酸化，从而减少细胞迁移。这项研究还提出了新的机制，可能为基于表观遗传因子 EZH2 和/或其靶基因的抑制的 CRC 治疗提供新的抗转移策略。
Reorganization of cytoskeleton via actin remodeling is a basic step of cell locomotion. Although cell migration of normal and cancer cells can be stimulated by a variety of intra- and extra-cellular factors, all paths ultimate on the regulation of cofilin activity. Cofilin is a small actin-binding protein able to bind both forms of actin, globular and filament, and is regulated by phosphorylation at Serine 3. Following phosphorylation at serine 3 cofilin is inactive, therefore cannot bind actin molecules and cytoskeleton remodeling is impaired. The histone methyltransferase EZH2 is frequently over expressed in many tumour types including colorectal cancer (CRC). EZH2 over activity, which results in epigenetic gene-silencing, has been associated with many tumour properties including invasion, angiogenesis and metastasis but little is known about the underneath molecular mechanisms. Herein, we report that EZH2 is able to control cofilin activity and consequently cell locomotion of CRC cell lines through a non-conventional novel axis that involves integrin signaling. Indeed, we show how genetic and pharmacological inhibition (DZNep and GSK343) of EZH2 function produces hyper phosphorylation of cofilin and reduces cell migration. We previously demonstrated by chromatin immuno-precipitation that Integrin alpha 2 (ITGα2) expression is regulated by EZH2. In the present study we provide evidence that in EZH2-silenced cells the signaling activity of the de-repressed ITGα2 is able to increase cofilin phosphorylation, which in turn reduces cell migration. This study also proposes novel mechanisms that might provide new anti-metastatic strategies for CRC treatment based on the inhibition of the epigenetic factor EZH2 and/or its target gene.
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影响因子：
21.3
作者：
Gohla, A;Birkenfeld, J;Bokoch, GM
通讯作者：
Bokoch, GM
EZH2的下调降低了雌激素受体阴性侵入性乳腺癌的生长，需要BRCA1。
影响因子：
8
作者：
Gonzalez, M. E.;Li, X.;Toy, K.;DuPrie, M.;Ventura, A. C.;Banerjee, M.;Ljungman, M.;Merajver, S. D.;Kleer, C. G.
通讯作者：
Kleer, C. G.
DOI：
10.1083/jcb.147.2.401
发表时间：
1999-10-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ivaska J;Reunanen H;Westermarck J;Koivisto L;Kähäri VM;Heino J
通讯作者：
Heino J
影响因子：
11.2
作者：
Ren, Gang;Baritaki, Stavroula;Yeung, Kam C.
通讯作者：
Yeung, Kam C.
影响因子：
37.3
作者：
Makrodouli E;Oikonomou E;Koc M;Andera L;Sasazuki T;Shirasawa S;Pintzas A
通讯作者：
Pintzas A