YEATS4与KAT8互作维持组蛋白H4K16ac修饰促进膀胱癌细胞增殖的作用机制研究

膀胱癌恶性程度高，表观修饰及转录调节紊乱，目前尚无有效的靶向表观修饰分子的治疗策略。我们前期通过靶向表观遗传调控因子CRISPR-Cas9敲除文库筛选出YEATS4是膀胱癌细胞存活的必需基因之一。预实验显示：敲除YEATS4显著抑制膀胱癌生长；YEATS4与KAT8互作并互相稳定；敲除YEATS4显著降低KAT8蛋白表达、染色质结合及组蛋白H4K16ac修饰；KAT8乙酰化修饰YEATS4并维持其蛋白稳定性。本项目拟：阐明YEATS4与KAT8蛋白相互稳定的机制；研究YEATS4乙酰化修饰对其蛋白稳定性或结合H3K27ac活性的影响；明确YEATS4能否募集KAT8至染色质形成正反馈环；探索阻断YEATS4与KAT8相互作用能否抑制膀胱癌的生长。本项目的完成，将揭示膀胱癌中组蛋白修饰阅读器YEATS4与书写器KAT8互相正向调控并引起表观转录紊乱的新机制，可能为膀胱癌治疗提供新的策略。

Bladder cancer is characterized by a high degree of malignancy, epigenetic and transcriptional disorder without specific therapeutic targets for epigenetic modification molecules. By using CRISPR-based epigenetic screens，we have recently identified YEATS4 as one of the epigenetic regulators that essential for the viability of bladder cancer cells. Our preliminary results showed that depletion of YEATS4 significantly inhibited the proliferation of bladder cancer cells. YEATS4 interacted and stabilized with KAT8. Depletion of YEATS4 dramatically downregulated the expression of KAT8 protein and its chromatin enrichment and decreased the levels of histone H4K16ac. KAT8 acetylated YEATS4 and maintained its protein stability. This proposal aims to clarify the mechanism of mutually stabilization between YEATS4 and KAT8. To determine the effect of acetylation of YEATS4 by KAT8 on its protein stability or its ability to combine with histone H3K27ac. To investigate whether YEATS4 can act as a positive feedback to enhance the recruitment of KAT8 to chromatin. To explore whether it can effectively inhibit the proliferation of bladder cancer cells by disrupting the interaction of YEATS4 and KAT8. We believe that this proposal will reveal a new mechanism of how histone modification reader YEATS4 and writer KAT8 mutually positively regulates and therefore leads to epigenetic transcriptional disorder in bladder cancer, which may provide a new therapeutic strategy for bladder cancer.