N-末端alpha-乙酰转移酶D(NatD)催化组蛋白H4的N-末端发生alpha-乙酰化（Nt-ac-H4），其生物学功能目前尚不清楚。本项目拟以人三阴性乳腺癌细胞为主要研究对象，体内外系统分析NatD对乳腺癌细胞迁移、侵袭及转移能力的影响与组蛋白修饰标记动态变化、基因表达以及相关信号通路的关系，阐明NatD引发的Nt-ac-H4对FOXA2等重要下游分子基因表达的特异调控，从而调节三阴性乳腺癌细胞间质-上皮转化(MET)过程的新分子机制。此外，我们还将揭示SIRT家族分子介导Nt-ac-H4乙酰化消除的分子机制及其在乳腺癌转移调控中的作用。在此基础上，结合生物信息学、结构生物学等方法筛选干预Nt-ac-H4修饰从而抑制肿瘤发生发展的特异小分子化合物。本项目将为针对NatD作为一个潜在癌症治疗新靶点的临床研究打下良好基础。

N-terminal alpha-acetyltransferase NatD catalyzes N-terminal alpha-acetylation of histone H4 (Nt-ac-H4). However, the biological functions of this modification remain largely unknown so far. This project is going to dissect the dynamic processes by which Nt-ac-H4 and other related histone modifications control triple negative breast cancer （TNBC）cell migration, invasion and metastasis, and to reveal the key signal pathways involved, such as mesenchymal-epithelial transition (MET). We will resolve the specific gene regulation of Nt-ac-H4 mediated by NatD on FOXA2 and its crosstalk with other histone modifications. In addition, we will also identify the molecular mechanism by which Nt-ac-H4 is removed and its implication during breast cancer metastasis. Based on these results, combined with Bioinformatics and Structural Biology, the project is going to screen for the specific small molecules through inhibiting Nt-ac-H4 to prevent tumor progression.