Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis
Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis
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Profilin-2对Smad2和Smad3的表遗传调控促进肺癌生长和转移
DOI：
10.1038/ncomms9230
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发表时间：
2015-09-01
影响因子：
16.6
通讯作者：
Song, Jian-Guo
中科院分区：
文献类型：
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作者：
Tang, Yun-Neng;Ding, Wei-Qiao;Song, Jian-Guo
转化生长因子-β信号的改变与肿瘤的发生和发展有关。然而，这种改变背后的分子机制却知之甚少。在这里，我们发现Profilin-2(Pfn2)通过表观遗传学机制增加Smad2和Smad3的表达，并且Profilin-2和Smad的表达与肺癌患者的不良预后相关。Profilin-2的过度表达促进了肺癌的生长和转移，而Profilin-2的基因敲除则大大减少了肺癌的生长和转移。我们发现Profilin-2通过阻止HDAC1的核移位而抑制HDAC1向Smad2和Smad3启动子的招募，这是通过这两种蛋白质C端的蛋白质-蛋白质相互作用导致Smad2和Smad3的转录激活而实现的。Smad2和Smad3表达增加可增强转化生长因子β1诱导的内皮细胞转化和血管生成因子VEGF和CTGF的产生。这些发现揭示了转化生长因子-β1/Smad信号的一种新的调控机制，并为抗癌药物的开发提供了潜在的分子靶点。
Altered transforming growth factor-beta (TGF-beta) signalling has been implicated in tumour development and progression. However, the molecular mechanism behind this alteration is poorly understood. Here we show that profilin-2 (Pfn2) increases Smad2 and Smad3 expression via an epigenetic mechanism, and that profilin-2 and Smad expression correlate with an unfavourable prognosis of lung cancer patients. Profilin-2 overexpression promotes, whereas profilin-2 knockdown drastically reduces, lung cancer growth and metastasis. We show that profilin-2 suppresses the recruitment of HDAC1 to Smad2 and Smad3 promoters by preventing nuclear translocation of HDAC1 through protein-protein interaction at the C terminus of both proteins, leading to the transcriptional activation of Smad2 and Smad3. Increased Smad2 and Smad3 expression enhances TGF-beta 1-induced EMT and production of the angiogenic factors VEGF and CTGF. These findings reveal a new regulatory mechanism of TGF-beta 1/Smad signalling, and suggest a potential molecular target for the development of anticancer drugs.