The E2F activators control multiple mitotic regulators and maintain genomic integrity through Sgo1 and BubR1.
The E2F activators control multiple mitotic regulators and maintain genomic integrity through Sgo1 and BubR1.
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DOI：
10.18632/oncotarget.20765
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发表时间：
2017-09-29
期刊：
影响因子：
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通讯作者：
Saavedra HI
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文献类型：
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作者：
Lee M;Rivera-Rivera Y;Moreno CS;Saavedra HI
E2F1， E2F2和E2F3a转录激活因子控制增殖。然而，E2F激活因子如何调节有丝分裂以维持基因组完整性尚不清楚。中心体扩增（CA）和无调节纺锤体组装检查点（SAC）是癌症非整倍体和染色体不稳定性（CIN）的主要产生因素。之前，我们发现过表达单个E2F激活因子可诱导乳腺上皮细胞中的CA和CIN，而在这里，我们发现E2F激活因子的联合过表达并不会增强CA。相反，E2F激活因子会升高多种有丝分裂调节因子的表达，包括Sgo1、Nek2、Hec1、BubR1和Mps1/TTK。TCGA数据库的cBioPortal分析显示，E2F在小叶浸润性乳腺肿瘤中的过表达与染色体分离、中心体稳态和SAC的多种调节因子的过表达相关。Kaplan-Meier图确定了E2F1、E2F3a、Mps1/TTK、Nek2、BubR1或Hec1的单独或联合过表达与乳腺癌患者较差的总生存率和无复发生存率之间的相关性。在共过表达E2Fs的MCF10A正常乳腺上皮细胞中，短暂的Sgo1敲低诱导CA，高比例的姐妹染色单体过早分离，染色体丢失，细胞凋亡增加，细胞克隆性降低。BubR1沉默导致没有CA的染色体丢失，表明Sgo1和BubR1通过两种不同的机制维持基因组完整性。我们的研究结果表明，乳腺上皮细胞中E2Fs的失调控激活可以通过sgo1依赖性有丝分裂检查点的激活来抵消。
The E2F1, E2F2, and E2F3a transcriptional activators control proliferation. However, how the E2F activators regulate mitosis to maintain genomic integrity is unclear. Centrosome amplification (CA) and unregulated spindle assembly checkpoint (SAC) are major generators of aneuploidy and chromosome instability (CIN) in cancer. Previously, we showed that overexpression of single E2F activators induced CA and CIN in mammary epithelial cells, and here we show that combined overexpression of E2F activators did not enhance CA. Instead, the E2F activators elevated expression of multiple mitotic regulators, including Sgo1, Nek2, Hec1, BubR1, and Mps1/TTK. cBioPortal analyses of the TCGA database showed that E2F overexpression in lobular invasive breast tumors correlates with overexpression of multiple regulators of chromosome segregation, centrosome homeostasis, and the SAC. Kaplan-Meier plots identified correlations between individual or combined overexpression of E2F1, E2F3a, Mps1/TTK, Nek2, BubR1, or Hec1 and poor overall and relapse-free survival of breast cancer patients. In MCF10A normal mammary epithelial cells co-overexpressing E2Fs, transient Sgo1 knockdown induced CA, high percentages of premature sister chromatid separation, chromosome losses, increased apoptosis, and decreased cell clonogenicity. BubR1 silencing resulted in chromosome losses without CA, demonstrating that Sgo1 and BubR1 maintain genomic integrity through two distinct mechanisms. Our results suggest that deregulated activation of the E2Fs in mammary epithelial cells is counteracted by activation of a Sgo1-dependent mitotic checkpoint.