雌激素受体介导的染色质修饰的可塑性及对细胞代谢的影响和在乳腺癌发生发展中的作用

The tight connection between epigenetics and metabolism is manifested mainly in two ways: on one hand, chemical modifications of histones and DNA are important epigenetic mechanisms to regulate the expression of key metabolic enzymes; on the other hand, many of the enzymes that add or remove such chemical modifications are known, or might be suspected, to be sensitive to changes in intracellular metabolism. Epigenetic deregulation often leads to altered metabolism and contributes to the progression of various cancers. Estrogen receptor alpha (ERα) is a classical etiology factor in the initiation and progression of breast cancer. The transcription plasticity regulated by ERα in breast cancer cells involves protein co-factors that contribute to the modification and remodeling chromatin structure. However, the intrinsic activity of several well-known co-factors that are involved in ERα-regulated gene transcription is not well defined and the impact of estrogen signaling on cell metabolisms thus on the initiation/progression of breast cancer are not fully understood. We propose to explore the mechanisms underlying and the biological significance of the plasticity of ERα-regulated gene transcription by investigating the following three issues: 1) whether ERα-associated histone acetyltransferases, such as CBP/p300/PCAF and p160 co-factor proteins have other enzymatic activities, and if so how they contribute to ERα-regulated gene transcription and chromatin remodeling events; 2) what is the molecular basis of FOXA1 in pioneering competency and epigenetic reprogramming in ERα-mediated gene transcriptional regulation; 3) how ERα and its associate epigenetic factors play a role in metabolic reprogramming in breast cancer cells, and how altered metabolism affects epigenetic states. Collectively, we envision that the furtherance in understanding of the molecular mechanisms governing ERα-regulated gene transcription, in combination with the elucidation of the connection between chromatin regulators and cell metabolism in estrogen signaling pathway, will improve anti-cancer drug design and benefit the therapeutic pursuits for breast cancer.

染色质修饰与细胞代谢密切相关。染色质修饰异常所导致的表观遗传调控失衡可影响多种代谢酶的表达，最终可致使代谢途径改变和细胞癌变；另一方面，多种染色质修饰因子（酶）依赖代谢中间产物作为辅助因子而发挥活性，代谢紊乱可加剧染色质修饰异常。作为乳腺癌发生发展的经典病因学因子，雌激素受体ERα激活基因转录需通过“先锋因子”FOXA1及多种染色质修饰因子的协同而实现。本项目拟从以下方面探讨ERα介导的染色质修饰可塑性及其对细胞代谢的影响和在乳腺癌发生发展中的作用：1）经典的ERα相关染色质修饰因子p160家族和CBP/p300/PCAF究竟有何组蛋白修饰酶活性；2）FOXA1在ERα介导的转录调控中怎样发挥 “先锋”作用; 3）ERα介导的基因转录调控及染色质重塑与乳腺癌细胞代谢如何相互影响。阐明上述问题有助于我们深入认识表观遗传调控与细胞代谢的关系，为乳腺癌的发病机制研究及靶向治疗提供新的线索。

染色质修饰与细胞代谢密切相关。染色质修饰异常所导致的表观遗传调控失衡可影响多种代谢酶的表达，最终可致使代谢途径改变和细胞癌变；另一方面，多种染色质修饰因子（酶）依赖代谢中间产物作为辅助因子而发挥活性，代谢紊乱可加剧染色质修饰异常。作为乳腺癌发生发展的经典病因学因子，雌激素受体ERα激活基因转录需通过“先锋因子”FOXA1及多种染色质修饰因子的协同而实现。在本项目的支持下，本课题组证明了FOXA1通过参与DNA主动去甲基化而影响染色质开放状态及雌激素受体转录通路，鉴定了多个参与肿瘤发展的调控组蛋白琥珀酰化、巴豆酰化、去泛素化等的酶及分子，并对参与雌激素受体转录调控的转录因子、lncRNA、组蛋白修饰酶等在乳腺癌发生发展中的功能进行了系统性研究。项目组在有影响力的国际主流学术期刊发表论文共12篇，其中影响因子大于20的论文篇，影响因子大于10的论文九篇。