Altered transforming growth factor-β (TGF-β) 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-β1-induced EMT and production of the angiogenic factors VEGF and CTGF. These findings reveal a new regulatory mechanism of TGF-β1/Smad signalling, and suggest a potential molecular target for the development of anticancer drugs.

中文翻译：

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profilin-2对Smad2和Smad3的表观遗传调控可促进肺癌的生长和转移。

改变的转化生长因子-β（TGF-β）信号转导与肿瘤的发生和发展有关。但是，这种改变背后的分子机制了解甚少。在这里，我们显示profilin-2（Pfn2）通过表观遗传机制增加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的过表达促进了肺癌的生长和转移，而profilin-2的敲低则大大降低了肺癌的生长和转移。我们表明，profilin-2通过阻止HDAC1通过两种蛋白质C末端的蛋白质-蛋白质相互作用，导致Hmad1的核转位，从而抑制HDAC1向Smad2和Smad3启动子的募集，从而导致Smad2和Smad3的转录激活。Smad2和Smad3表达的增加增强了TGF-β1诱导的EMT和血管生成因子VEGF和CTGF的产生。这些发现揭示了TGF-β1/ Smad信号传导的新调节机制，并提出了开发抗癌药物的潜在分子靶标。