转录因子Snail乙酰化修饰在肝癌EMT过程中的作用及其调控机制

Hepatic carcinoma is a common malignancy, the fatality rate of this carcinoma is very high because it is very easily and earlier generate invasion and metastasis. Recent studies indicate that epithelial-mesenchymal transition(EMT) is the driving force of invasion and metastasis for hepatic carcinoma cells, during the process of EMT in hepatic carcinoma, the transcription factor Snail is at a high acetylation status persistently, the acetylation of Snail inhibits its ubiquitination and significantly raised its transcriptional activity, which indicating that acetylation of snail plays a key regulatory role in EMT of hepatic carcinoma. Therefore, on the basis of our previous research, the major objectives of the present proposal are to identify acetylation modification sites and related deacetylase of transcription factors snail. Furthermore, we will also identify the snail ubiquitination sites and the signaling pathway proteins which regulating the EMT of hepatic carcinoma regulated by acetylation of Snail, demonstrating the molecular events of EMT which regulated by post-translational modifications of Snail in hepatic carcinoma cells, revealing the role of snail that regulated by acetylation-ubiquitination to induction of EMT in hepatic carcinoma and to explore the influence on EMT in hepatic carcinoma by targeting inhibition of Snail, in which we propose to elucidate the key role and molecular mechanism of transcription factors snail acetylation in regulating the EMT of hepatic carcinoma, ultimately provides important foundation for prevention and treatment of hepatic carcinoma.

肝癌是常见的恶性肿瘤，由于极易出现侵袭与转移，因此病死率非常高。肝癌上皮间质化（EMT）是驱使肝癌细胞侵袭与转移的原动力，最近研究表明EMT关键转录因子Snail在肝癌EMT过程中持续处于高乙酰化状态，Snail乙酰化后可抑制其泛素化降解并显著上调其转录活性，提示Snail的乙酰化修饰在肝癌EMT过程中起着关键作用。因此本课题拟在前期研究基础上，鉴定转录因子Snail乙酰化修饰位点及相关乙酰化酶，确证受乙酰化修饰调控的Snail泛素化位点和肝癌EMT过程中的信号通路蛋白，解析肝癌EMT过程中调控Snail翻译后修饰的相关分子事件，揭示Snail乙酰化-泛素化相互作用在肝癌EMT中作用，并探讨靶向抑制Snail乙酰化对肝癌EMT的影响，从而阐明Snail乙酰化修饰参与调控肝癌EMT的作用及其分子机制，以期为肝癌的防治提供重要的研究基础。

肝癌是常见的恶性肿瘤，由于极易出现侵袭与转移，病死率非常高。肝癌上皮间质化（EMT）是驱使肝癌细胞侵袭与转移的原动力，因此研究调控肝癌EMT的分子机制以及寻找干预EMT的策略对于肝癌的防治具有非常重要的意义。在本课题研究中，我们以组蛋白去乙酰化酶抑制剂 (histone deacetylase inhibitors, HDACi)中的SAHA和NaB构建肝癌EMT模型，研究发现转录因子Snail在肝癌EMT的发生发展中发挥关键调控作用，并且发现Snail乙酰化修饰可明显延缓肝癌细胞Snail蛋白降解，HDACi（SAHA, NaB）可能通过诱导CSN2高表达与Snail结合，促进Snail的乙酰化，封闭其磷酸化和泛素化位点从而抑制其通过泛素-蛋白酶体途径降解来维持Snail蛋白的稳定性，使Snail蛋白水平保持高水平而促进肝癌细胞的EMT发生。同时，在转录前水平我们发现Smads信号通路是诱导Snail转录表达上调的关键信号通路。从而阐明了Snail表达的调控机制，以及Snail乙酰化对其泛素化、蛋白稳定性及肝癌EMT发生的影响，同时鉴定Snail乙酰化修饰调控肝癌EMT过程中的关键信号通路蛋白，从而解析了Snail表达及其乙酰化修饰调控肝癌EMT的分子机制，为肝癌防治提供研究基础，具有非常重要的科学价值和潜在应用前景。