BPTF介导的染色质重塑增强AR调控Snail转录促进胃癌侵袭转移的分子机制研究

肿瘤的侵袭转移是胃癌患者死亡的主要原因。我们前期研究发现，胃癌组织中雄激素受体（AR）、BPTF高表达，且其二者表达水平与Snail表达正相关。已知Snail是EMT关键转录因子，可促进肿瘤细胞侵袭转移，但是其表达调控机制尚不清楚。本项目拟在前期研究的基础上，研究AR招募染色质重塑复合物MLL1-WDR5介导组蛋白H4K16甲基化和乙酰化修饰，BPTF与H4K16ac、H3K4me3结合使Snail增强子与启动子相互靠近形成环袢，发挥染色质重塑作用，增加局部染色质可接近性，形成转录调控复合物BPTF/AR/WLL1-WDR5/RNAPII，增强AR对下游基因Snail的转录活性，上调Snail表达，诱导胃癌细胞发生EMT，促进胃癌细胞侵袭转移。基于此，对关键节点进行干预，以期抑制胃癌侵袭转移。本项目将为进一步理解胃癌侵袭转移机制，探索胃癌侵袭转移治疗新方法提供理论与实验依据。

Tumor invasion and metastasis is the leading cause of death in patients with gastric cancer. Our previous study found that the expression of androgen receptor (AR) and Bromodomain PHD-Finger Transcription Factor (BPTF) were upregulated and positively correlated with Snail expression in GC tissue. Snail could induce epithelial-mesenchymal transition（EMT）and promote tumor cells invasion and metastasis. But, the mechanisms of regulation Snail expression are unclear. Based on the previous findings, in this project we will illustrate scientific hypothesis as follows. AR recruits chromatin remodeling complex MLL1-WDR5 to mediate histone H4K16 acetylation and methylation. BPTF may combine with H3K4me3 and H4K16ac and bind with AR forming AR/BPTF/MLL1-WDR5/RNAPII, BPTF mediate enhancer and promoter interaction to enhance the transcriptional activity of AR on Snail and exert chromatin remodeling function to increase local chromatin accessibility. The up-regulated Snail may induce epithelial- mesenchymal transition promote invasion and metastasis of gastric cancer cells. Based on this theory, we will develop new therapeutic strategies to tumor invasion and metastasis by perturbation the key regulators. This project will provide evidence for further understanding the mechanism of invasion and metastasis and developing a new strategies for the treatment of invasion and metastasis of gastric cancer.