SENP5 mediates breast cancer invasion via a TGFβRI SUMOylation cascade.
SENP5 mediates breast cancer invasion via a TGFβRI SUMOylation cascade.
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DOI：
10.18632/oncotarget.1783
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发表时间：
2014-02-28
期刊：
影响因子：
--
通讯作者：
Efroni S
中科院分区：
文献类型：
--
作者：
Cashman R;Cohen H;Ben-Hamo R;Zilberberg A;Efroni S
确定乳腺癌生物学核心的新机制至关重要。这些机制可以解释对治疗的反应，揭示新的靶点或驱动检测分析。为了揭示这种新机制，我们对包含 1363 名患者的基因表达数据集进行了生存分析。通过迭代基因概要，我们筛选了它们作为预后生物标志物的重要性，并确定了 SUMO 特异性蛋白酶 5 (SENP5)，以在五个不相关的测试数据集中将患者显着分为两个生存组。根据这些发现，SENP5 的低表达与乳腺癌患者的良好预后相关。根据这些发现，我们分析了 SENP5 沉默，并表明它随后抑制了乳腺癌细胞系中不依赖贴壁的生长、增殖、迁移和侵袭。我们进一步表明这些变化是通过调节 TGFβRI 水平来实现的。这些数据与最近有关 TGFβRI SUMOylation 的报道相关。 TGFβRI 表达发生变化后，我们发现其靶基因之一 MMP9 在细胞外基质降解中起关键作用，并有助于 TGFβ 诱导的侵袭，在 SENP5 沉默后显着下调。这是第一份关于 SENP5-TGFβ-MMP9 级联及其参与乳腺癌机制的报告。
Identifying novel mechanisms, which are at the core of breast cancer biology, is of critical importance. Such mechanisms may explain response to treatment, reveal novel targets or drive detection assays. To uncover such novel mechanisms, we used survival analysis on gene expression datasets encompassing 1363 patients. By iterating over the compendia of genes, we screened for their significance as prognosis biomarkers and identified SUMO-specific protease 5 (SENP5) to significantly stratify patients into two survival groups across five unrelated tested datasets. According to these findings, low expression of SENP5 is associated with good prognosis among breast cancer patients. Following these findings, we analyzed SENP5 silencing and show it is followed by inhibition of anchorage-independence growth, proliferation, migration and invasion in breast cancer cell lines. We further show that these changes are conducted via regulation of TGFβRI levels. These data relate to recent reports about the SUMOylation of TGFβRI. Following TGFβRI changes in expression, we show that one of its target genes, MMP9, which plays a key role in degrading the extracellular matrix and contributes to TGFβ-induced invasion, is dramatically down regulated upon SENP5 silencing. This is the first report represents SENP5-TGFβ-MMP9 cascade and its mechanistic involvement in breast cancer.
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