题目：On the novel mechanism and selectivity of anthracycline drugs

报告人：庞宝旭 荷兰莱顿大学医学中心

时间：2018年9月5日（周三）13:30

地点：新民校区第二教学楼2103室

主办单位：白求恩医学部

报告人简介：

2013年博士毕业于荷兰癌症研究所，2013-2014年在荷兰癌症研究所从事博士后工作，2014年至2018年，在斯坦福大学医学院遗传系从事博士后工作。2017年10月至今在荷兰莱顿大学医学中心化学和细胞生物学系担任助理教授。博士工作期间，基于蒽环化疗药物，发现并定义了一种全新的药物作用机制－药物直接介导组蛋白从染色质的脱离，从而影响细胞的表冠遗传学和对DNA损伤的修复。相关研究结果以第一作者或共同通讯作者发表在《Nature Communications》, 《Cancer Research 》,《Nature Chemical Biology 》等杂志。博士后工作期间研发两种高通量筛选系统对基因组非编码调节区的功能进行研究。博士科研期间获得荷兰Antoni van Leeuwenhoek Prize奖和国家优秀自费留学生奖学金。现在实验室被荷兰LUMC Gisela Thier Fellowship和KWF Young Investigator Award资助。

报告摘要：

DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. We identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. Histone eviction attenuated DNA repair and deregulated the transcriptome in cancer cells and organs such as the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in patients. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription, side effects and cancer therapy. In addition, we performed genome-wide high-resolution mapping of chemotherapeutic effects of various topoisomerase I and II (TopoI and II) inhibitors and integrated this mapping with established maps of genomic or epigenomic features to show their activities in different genomic regions. We show that aclarubicin, has a different genomic specificity and evicts histones from H3K27me3-marked heterochromatin, with consequences for diffuse large B-cell lymphoma cells with elevated levels of H3K27me3. Modifying anthracycline structures may yield compounds with selectivity for different genomic regions and activity for different tumor types.