乳腺癌中组蛋白修饰介导Ras通路信号传递的机制与功能研究

Whether epigenetic modifications are functionally linked with human tumor-related signaling pathways remains unclear. Based on the previous work，we aim to study how apparent histone modifications, such as -H3K9ac and H4K16ac, affect the occurrence and progression of breast cancer. We will use human breast cancer cell lines, human breast tumor tissues as models, and will focus on the participation of histone modification in modulating Ras signaling pathway. We will investigate the molecular networks that are up and downstream of histone modifications, and study how histone-modifying enzymes are involved in the occurrence and progression of human breast cancer through analyzing the "histone code" of methylation, acetylation. We will also analyze whether these histone modification sites can be developed as targets for cancer therapy. The project consists of three sections: 1) Confirm the regulatory relationship between the Ras signaling pathway and histone modifications; 2) Research the mechanisms by which Ras signaling pathway regulate histone modifications; detect interacting proteins and determine their effects; 3) Interpret the specific role of histone modification in tumor heterogenization (including the determination of signal transduction pathways that act downstream of histone modifications). The goals of our research: 1) Clarify the molecular mechanisms by which Ras signaling pathway regulate the levels of histone modification; 2) Clarify which changes to cell function that occur during breast cancer occurrence and progression are regulated by histone modifications; 3) Identify specific molecular mechanisms by which histone modifications regulate tumor-related cell biology changes.

表观遗传修饰如何介导致瘤信号传递是肿瘤研究的热点之一。本项目在前期工作基础上，拟以组蛋白修饰参与Ras信号通路的信号传递过程为主线，研究与该通路异常相关的乳腺癌发生、发展过程中H3K9ac和H4K16ac等表观遗传因素所起作用。 课题内容包括：1）确认Ras通路与组蛋白修饰的调控关系；2）解析组蛋白修饰参与乳腺癌形成的具体作用和机制，即由组蛋白修饰传递的Ras信号的功能及途径；3）信号通路调控组蛋白修饰的机制研究，检测作用蛋白及方式。 我们的研究目标是：1）阐明Ras信号通路调控组蛋白修饰水平的分子机制；2）明确组蛋白修饰参与调控乳腺肿瘤发生、发展过程中的哪些细胞生物学功能变化；3）证实组蛋白修饰参与调控肿瘤相关细胞生物学改变的分子机理。

乳腺癌是女性常见的恶性肿瘤之一，严重威胁着女性的健康。经过不断探索，研究人员揭示出：乳腺癌不仅仅是由基因突变导致原癌基因激活或抑癌基因失活而引起的一种疾病。DNA序列以外的其他可遗传信息的改变，如表观遗传修饰，也可以导致乳腺癌发生，并促进其恶性进展。表观遗传学修饰与乳腺癌发生、发展的关系以及在诊断和治疗领域的应用成为了当今肿瘤学领域的研究热点。表观遗传修饰如何介导致瘤信号传递是亟待解决的问题之一。.本项目以组蛋白修饰参与Ras通路的信号传递过程为主线，研究与该通路异常相关的乳腺癌发生、发展过程中H3K9ac和H4K16ac等表观遗传因素所起作用。 研究内容包括：1）确认Ras通路与组蛋白修饰的调控关系；2）解析组蛋白修饰参与乳腺癌发生、发展的作用和机理；3）信号通路调控组蛋白修饰的机制。 .经研究，项目组验证了Ras通路调控组蛋白修饰的两条信号轴：.1）Ras-ERK1/2-PCAF/WSTF/MOF-H3K9ac/H4K16ac.MOF（males absent on the first）和PCAF（p300/CBP-associated factor）的乙酰化酶活性的发挥依赖于PCAF/WSTF/MOF复合物的形成，由WSTF介导其与H3/H4结合并发生乙酰化反应。Ras-ERK1/2（extracellular signal-regulated kinases 1/2）通路激活后引起WSTF第158位丝氨酸残基磷酸化水平升高，促使MOF从复合物解离，而PCAF与WSTF的结合量增加，进而引起MOF与H4亲和力降低，而PCAF与H3亲和力增加，最终导致H4K16ac下调，同时H3K9ac上调。.2）Ras-ERK1/2-NIC1-MDM2-MOF-H4K16ac.Ras-ERK1/2激活后可引起Notch1通路活性增强，即NIC1（Notch1 intracellular domain）水平增加，进而引起泛素连接酶MDM2（murine double minute 2）过表达并诱导MOF降解，导致H4K16ac下调。 .上述两条信号轴的异常激活可引起下游靶基因表达发生改变，增强癌细胞增殖、迁移能力，最终促进乳腺癌发生、发展。本项目所取得的成果阐明了H3K9ac和H4K16ac调控乳腺癌发生、发展的分子机制，为临床诊疗提供了新靶点。