MKL1 links epigenetic activation of MMP2 to ovarian cancer cell migration and invasion
MKL1 links epigenetic activation of MMP2 to ovarian cancer cell migration and invasion
复制标题
MKL1 将 MMP2 的表观遗传激活与卵巢癌细胞迁移和侵袭联系起来
DOI：
10.1016/j.bbrc.2017.04.006
复制
发表时间：
2017-06-03
影响因子：
3.1
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Xu, Wenping;Xu, Huihui;Xu, Yong
癌细胞对低氧压等促进转移的信号做出反应，会发展出几种不同的策略来促进迁移和侵袭。在这个过程中，基质金属蛋白酶(MMPs)的表达水平被上调，从而使癌细胞能够更容易地进入或离开循环。在这份报告中，我们显示转录调节因子MKL1的信息水平在人类恶性卵巢癌组织中升高，而与更良性的卵巢癌组织相比，伴随着类似的MMP2表达变化。MKL1沉默可阻断低氧诱导的卵巢癌细胞(SKOV-3)体外迁移和侵袭。在SKOV-3细胞中，MKL1的过度表达被激活，而MKL1缺失则抑制MMP2的转录。MKL1被核因子-kappaB募集到MMP2启动子，以响应低氧。从机制上讲，MKL1招募了组蛋白甲基转移酶SET1和染色质重塑蛋白BRG1，并协调它们的相互作用来改变MMP2启动子周围的染色质结构，导致转录激活。BRG1和SET1都是低氧诱导MMP2反式激活所必需的。最后，SET1和BRG1的表达水平与人类卵巢癌恶性肿瘤呈正相关。总之，我们的数据表明，MKL1通过表观基因激活MMP2转录促进卵巢癌细胞的迁移和侵袭。(C)2017 Elsevier Inc.保留所有权利。
Responding to pro-metastatic cues such as low oxygen tension, cancer cells develop several different strategies to facilitate migration and invasion. During this process, expression levels of matrix metalloproteinases (MMPs) are up-regulated so that cancer cells can more easily enter or exit the circulation. In this report we show that message levels of the transcriptional modulator MKL1 were elevated in malignant forms of ovarian cancer tissues in humans when compared to more benign forms accompanying a similar change in MMP2 expression. MKL1 silencing blocked hypoxia-induced migration and invasion of ovarian cancer cells (SKOV-3) in vitro. Over-expression of MKL1 activated while MKL1 depletion repressed MMP2 transcription in SKOV-3 cells. MKL1 was recruited to the MMP2 promoter by NF-kappa B in response to hypoxia. Mechanistically, MKL1 recruited a histone methyltransferase, SET1, and a chromatin remodeling protein, BRG1, and coordinated their interaction to alter the chromatin structure surrounding the MMP2 promoter leading to transcriptional activation. Both BRG1 and SET1 were essential for hypoxia-induced MMP2 trans-activation. Finally, expression levels of SET1 and BRG1 were positively correlated with ovarian cancer malignancies in humans. Together, our data suggest that MKL1 promotes ovarian cancer cell migration and invasion by epigenetically activating MMP2 transcription. (C) 2017 Elsevier Inc. All rights reserved.