State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Elife. 2019 May 3;8:e44306. doi: 10.7554/eLife.44306.
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.
PAX8 是卵巢上皮性癌中的一种原型谱系存活致癌基因。然而，其潜在的促肿瘤发生机制及其潜在的治疗意义尚未得到充分阐明。在这里，我们使用改良的癌症异常分布分析，鉴定了一个卵巢谱系特异性的 PAX8 调控网络，其中 PAX8-FGF18 轴负责以自分泌的方式促进细胞迁移。基于图像的药物筛选发现，组蛋白去乙酰化酶（HDACs）的小分子抑制剂能够强烈抑制 PAX8 的表达。从机制上讲，HDAC 阻断改变了组蛋白 H3K27 的乙酰化占有率，并扰乱了与 PAX8 基因座相关的超级增强子拓扑结构，导致 PAX8 转录本和相关靶基因的表观遗传下调。HDAC 拮抗剂作为单一药物有效地抑制了卵巢肿瘤的生长和扩散，并与标准化疗联合发挥协同作用。这些发现为依赖 PAX8 的卵巢癌提供了机制和治疗上的见解。更普遍地说，我们的分析和实验方法为在各种人类恶性肿瘤中识别和靶向谱系存活致癌基因提供了一个可扩展的范例。
