AKT的异常激活与乳腺癌的进展及治疗抵抗密切相关，对其分子调控网络的深入理解是提高此类抑制剂疗效的关键。多梳蛋白Mel-18是一个通过染色质修饰调控靶基因的转录抑制因子。我们研究发现AKT能与Mel-18结合，磷酸化其T334位点，并负性调控组蛋白H2A的泛素化水平。本课题拟通过研究AKT磷酸化Mel-18的T334调控组蛋白泛素化修饰的分子机制及其对乳腺癌细胞增殖、侵袭转移及肿瘤“干性”的影响，探讨这种磷酸化对乳腺癌患者病程进展、预后及治疗反应的预测作用。通过ChIP-Seq分析AKT介导的染色质修饰对Mel-18与靶基因DNA交互作用的影响，结合TCGA数据，采用基因优化法，找出AKT通路异常激活的乳腺癌患者新的潜在的治疗靶点；从这些靶基因中寻找合理的与AKT抑制剂的联用方案，并在乳腺癌动物模型上进行验证。本研究为深入理解AKT的分子调控网络及其在乳腺癌发生发展和诊治中的作用提供新策略

Aberrant AKT activation is highly related to tumor malignant progression and treatment resistance. Understanding the AKT signaling network is a key to improve the clinical therapeutic efficacy of AKT inhibition. Mel-18 is a member of the polycomb group (PcG) proteins, which suppresses gene expression by modulating the chromatin status of gene promoter region. In our preliminary study, we identified that Mel-18 contains a consensus substrate motif of AKT kinase. AKT interacts with and phosphorylates Mel-18 at Thr334, leading to specific downregulation of ubiquitination status at histone H2A lysine 119. In this proposal, we will focus on the biological and pathological effects of this novel regulatory mechanism. We will investigate the roles of AKT-mediated Mel-18 phosphorylation on the breast cancer cell proliferation, invasion and migration, and maintenance of cancer stem cell activity. We will also evaluate whether Mel-18 phosphorylation can serve as a cancer biomarker by analyzing the correlation of Mel-18 phosphorylation with breast cancer progression, prognosis and treatment response in breast cancer patients. Moreover, we will use ChIP-Seq to perform a comprehensive analysis of the effect of AKT-mediated chromatin modification on Mel-18 target gene profile. Combined with TCGA data, we will dig out potential therapeutic targets for breast cancer patients with the aberrant AKT activation by using Gene prioritization method. Finally, we will propose potential combinational therapeutic strategies by combining AKT inhibitors with inhibitors of these new targets, and validate their synergistic anti-tumor efficacy in breast cancer animal models. Overall, this study will improve our understanding of the molecular regulation of AKT network and provide new combinational strategies for breast cancer treatment.