远处转移是NSCLC致死的主要原因，但其分子机制仍待深入研究。P300是一种组蛋白乙酰基转移酶，通过调控转录因子参与恶性肿瘤的发生发展。我们的前期研究发现p300表达与NSCLC远处转移相关，体外也证实p300高表达促进NSCLC细胞的迁移和侵袭能力，并发现p300能诱导NSCLC细胞发生EMT。进而我们还发现p300可调控NSCLC细胞Skp2的表达，且已有文献显示Skp2可降解E-cadherin。而E-cadherin下调是EMT的分子表型。由此我们提出：p300可能通过调控Skp2诱导EMT促进NSCLC远处转移。本项目将应用最新的体外培养系统和分子生物学手段，结合小鼠原位移植瘤模型，获得p300高表达诱导EMT促进NSCLC远处转移的可靠证据，寻找并证实此过程中p300直接作用的分子和信号通路，阐明p300促进NSCLC远处转移的机制，为研发NSCLC靶向治疗药物提供新的思路。

Distant metastasis is the main cause of death in patients with NSCLC, but the molecular mechnisms are far from clearly elucidated. P300, a histone acetyltransferase, is involved in regulating many transcription factors and tumorgenesis of human malignancies. Our previous studies demonstrated that p300 expression associated with distant metastasis in human NSCLC, in vitro assays also demonstrated that over expression of p300 promoted cell migration and invasion in NSCLC cell lines, and furtherly showed that p300 could induce EMT in NSCLC. Our recent study found that p300 regulated the stability of Skp2 in NSCLC cell lines, while other studies in literature reported Skp2 was involved in degration of E-cadherin, whose down-regulation is the molecular phenotype of EMT. Taken together, we suppose that p300 may promote distant mestatastasis of NSCLC by regulating Skp2 to inducing EMT. In this project, we will use the newly advanced in vitro cell culturing system and molecular biological techniques, combined with orthotopic implantation of lung cancer in mice, to demonstrate the function of p300 in inducing EMT and promoting distant metastasis, to identify the moleculars and signaling pathways that directly interacting with p300, and elucidate the mechanisms of p300 in promoting distant metastasis of NSCLC, with the purpose to find potential molecular targets for the treatment of NSCLC.