The transcriptional induction of PIK3CA in tumor cells is dependent on the oncoprotein Y-box binding protein-1
The transcriptional induction of PIK3CA in tumor cells is dependent on the oncoprotein Y-box binding protein-1
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DOI：
10.1038/onc.2009.81
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发表时间：
2009-06-01
期刊：
影响因子：
8
通讯作者：
Dunn, S. E.
中科院分区：
文献类型：
--
作者：
Astanehe, A.;Finkbeiner, M. R.;Dunn, S. E.
PIK 3CA编码磷脂酰肌醇-3-激酶（PI 3 K）的p110 α催化亚基，被认为是一种致癌基因。尽管PIK 3CA在癌症中很重要，但人们对是什么促使其在肿瘤细胞中表达知之甚少。我们最近的特点PIK 3CA启动子，并报告说，它是转录沉默的肿瘤抑制蛋白p53。在本研究中，我们证明了PIK 3CA可以由致癌转录因子Y-box结合蛋白-1（YB-1）诱导。使用染色质免疫沉淀和电泳迁移率变动分析在PIK 3CA启动子上鉴定了三个YB-1响应元件。有趣的是，在基底细胞样乳腺癌模型中用siRNA沉默YB-1降低了p110 α蛋白水平，无论PIK 3CA是野生型、扩增型还是突变型。p110 α的这种降低导致PI 3 K活性的降低以及主要通过p90核糖体S6激酶和S6核糖体蛋白的下游信号传导。PIK 3CA依赖性信号传导的中断抑制与尿激酶纤溶酶原激活物（uPA）的损失相关的细胞侵袭。类似地，沉默YB-1抑制侵袭和uPA产生，然而这通过引入组成型活性PIK 3CA是可逆的。总之，YB-1是第一个报道的通过其启动子的转录控制来诱导PIK 3CA表达的癌基因。Oncogene（2009）28，2406-2418; doi：10.1038/onc.2009.81; 2009年5月11日在线发表
PIK3CA, which codes for the p110 alpha catalytic subunit of phosphatidylinositol-3-kinase (PI3K), is implicated as an oncogene. Despite importance of PIK3CA in cancer, little is known about what drives up its expression in tumor cells. We recently characterized the PIK3CA promoter and reported that it is transcriptionally silenced by the tumor suppressor protein p53. In the present study, we demonstrate that PIK3CA can be induced by the oncogenic transcription factor Y-box binding protein-1(YB-1). Three YB-1-responsive elements were identified on the PIK3CA promoter using chromatin immunoprecipitation and electrophoretic mobility shift assays. Interestingly, silencing YB-1 with siRNA in models of basal-like breast cancer decreased p110 alpha protein levels regardless of whether PIK3CA was wild type, amplified or mutated. This decrease in p110 alpha led to a reduction in PI3K activity and the downstream signaling primarily through p90 ribosomal S6 kinase and S6 ribosomal protein. Disruption in PIK3CA-dependent signaling suppressed cellular invasion correlative with loss of urokinase plasminogen activator (uPA). Similarly, silencing YB-1 suppressed invasion and uPA production however this was reversible through the introduction of constitutively active PIK3CA. In conclusion, YB-1 is the first reported oncogene to induce the expression of PIK3CA through transcriptional control of its promoter. Oncogene (2009) 28, 2406-2418; doi:10.1038/onc.2009.81; published online 11 May 2009