Lysine Acetyltransferase GCN5 Potentiates the Growth of Non-small Cell Lung Cancer via Promotion of E2F1, Cyclin D1, and Cyclin E1 Expression
Lysine Acetyltransferase GCN5 Potentiates the Growth of Non-small Cell Lung Cancer via Promotion of E2F1, Cyclin D1, and Cyclin E1 Expression
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赖氨酸乙酰转移酶 GCN5 通过促进 E2F1、Cyclin D1 和 Cyclin E1 表达增强非小细胞肺癌的生长
DOI：
10.1074/jbc.m113.458737
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发表时间：
2013-05-17
影响因子：
4.8
通讯作者：
Kang, Jiuhong
中科院分区：
文献类型：
--
作者：
Chen, Long;Wei, Tingyi;Kang, Jiuhong
赖氨酸乙酰转移酶在癌症的发生发展中起着关键而复杂的作用。GCN5是一种赖氨酸乙酰转移酶，通常调节基因的表达，但它在癌症发展中的作用仍然很大程度上尚不清楚。在这项研究中，我们报告了GCN5在非小细胞肺癌组织中的高表达，并且它的表达与肿瘤大小有关。我们发现在多个肺癌细胞系中，GCN5的表达促进了细胞的生长和G(1)/S期的转变。进一步的研究发现，GCN5调节E2F1、细胞周期蛋白D1和细胞周期蛋白E1的表达。我们的记者分析表明，GCN5的表达增强了E2F1、细胞周期蛋白D1和细胞周期蛋白E1启动子的活性。芯片实验表明，GCN5直接与这些启动子结合，并增加了这些区域内组蛋白乙酰化的程度。机制研究表明，GCN5与E2F1相互作用，并被E2F1招募到E2F1、细胞周期蛋白D1和细胞周期蛋白E1启动子中。肺癌细胞中GCN5的功能被E2F1基因敲除。最后，我们证实了GCN5调节E2F1、细胞周期蛋白D1和细胞周期蛋白E1的表达，并在小鼠肿瘤模型中促进肺癌细胞的生长。综上所述，我们的结果表明，GCN5通过以E2F1依赖的方式直接促进E2F1、细胞周期蛋白D1和细胞周期蛋白E1的表达，从而特异性地促进肺癌的生长。我们的研究确定了GCN5在肺癌发生发展中的一个独特和新的功能，并提示GCN5-E2F1相互作用可能是肺癌治疗的潜在靶点。
The lysine acetyltransferases play crucial but complex roles in cancer development. GCN5 is a lysine acetyltransferase that generally regulates gene expression, but its role in cancer development remains largely unknown. In this study, we report that GCN5 is highly expressed in non-small cell lung cancer tissues and that its expression correlates with tumor size. We found that the expression of GCN5 promotes cell growth and the G(1)/S phase transition in multiple lung cancer cell lines. Further study revealed that GCN5 regulates the expression of E2F1, cyclin D1, and cyclin E1. Our reporter assays indicated that the expression of GCN5 enhances the activities of the E2F1, cyclin D1, and cyclin E1 promoters. ChIP experiments suggested that GCN5 binds directly to these promoters and increases the extent of histone acetylation within these regions. Mechanistic studies suggested that GCN5 interacts with E2F1 and is recruited by E2F1 to the E2F1, cyclin D1, and cyclin E1 promoters. The function of GCN5 in lung cancer cells is abrogated by the knockdown of E2F1. Finally, we confirmed that GCN5 regulates the expression of E2F1, cyclin D1, and cyclin E1 and potentiates lung cancer cell growth in a mouse tumor model. Taken together, our results demonstrate that GCN5 specifically potentiates lung cancer growth by directly promoting the expression of E2F1, cyclin D1, and cyclin E1 in an E2F1-dependent manner. Our study identifies a specific and novel function of GCN5 in lung cancer development and suggests that the GCN5-E2F1 interaction represents a potential target for lung cancer treatment.