PAX8 regulon in human ovarian cancer links lineage dependency with epigenetic vulnerability to HDAC inhibitors
PAX8 regulon in human ovarian cancer links lineage dependency with epigenetic vulnerability to HDAC inhibitors
复制标题
人类卵巢癌中的 PAX8 调节子将谱系依赖性与 HDAC 抑制剂的表观遗传脆弱性联系起来
DOI：
10.7554/elife.44306
复制
发表时间：
2019-05-03
期刊：
影响因子：
7.7
通讯作者：
Zhuang, Guanglei
中科院分区：
文献类型：
--
作者：
Shi, Kaixuan;Yin, Xia;Zhuang, Guanglei
PAX8是上皮性卵巢癌的一个原型谱系存活癌基因。然而，其潜在的致瘤机制和潜在的治疗意义都没有得到充分阐明。在这里，我们使用改进的癌症异常值分析确定了卵巢谱系特异性PAX8调控子，其中PAX8- fgf18轴负责以自分泌方式促进细胞迁移。基于图像的药物筛选明确了PAX8的表达被抗组蛋白去乙酰化酶（hdac）的小分子有效抑制。机制上，HDAC阻断改变了组蛋白H3K27乙酰化占用，扰乱了与PAX8基因位点相关的超增强子拓扑结构，导致PAX8转录物和相关靶点的表观遗传下调。HDAC拮抗剂单用可有效抑制卵巢肿瘤的生长和扩散，与标准化疗联合可发挥协同作用。这些发现为pax8依赖性卵巢癌的机制和治疗提供了新的见解。更一般地说，我们的分析和实验方法代表了一种可扩展的范式，用于识别和靶向多种人类恶性肿瘤的谱系生存癌基因。
PAX8 is a prototype lineage-survival oncogene in epithelial ovarian cancer. However, neither its underlying pro-tumorigenic mechanisms nor potential therapeutic implications have been adequately elucidated. Here, we identified an ovarian lineage-specific PAX8 regulon using modified cancer outlier profile analysis, in which PAX8-FGF18 axis was responsible for promoting cell migration in an autocrine fashion. An image-based drug screen pinpointed that PAX8 expression was potently inhibited by small-molecules against histone deacetylases (HDACs). Mechanistically, HDAC blockade altered histone H3K27 acetylation occupancies and perturbed the super-enhancer topology associated with PAX8 gene locus, resulting in epigenetic downregulation of PAX8 transcripts and related targets. HDAC antagonists efficaciously suppressed ovarian tumor growth and spreading as single agents, and exerted synergistic effects in combination with standard chemotherapy. These findings provide mechanistic and therapeutic insights for PAX8-addicted ovarian cancer. More generally, our analytic and experimental approach represents an expandible paradigm for identifying and targeting lineage-survival oncogenes in diverse human malignancies.