Faculty of Medicine, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Mol Cancer Ther. 2017 Dec;16(12):2656-2667. doi: 10.1158/1535-7163.MCT-17-0397. Epub 2017 Sep 6.
Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting the causative SS18-SSX fusion oncoprotein are currently available. Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell-cycle arrest, neuronal differentiation, and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb group targets were reactivated, including tumor suppressor , and proapoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and proapoptotic factors BIK, BIM, and BMF were important to apoptosis induction following HDAC inhibition in synovial sarcoma. HDAC inhibitor pathway activation results in apoptosis and decreased tumor burden following a 7-day quisinostat treatment in the mouse model of synovial sarcoma. This study provides mechanistic support for a particular susceptibility of synovial sarcoma to HDAC inhibition as a means of clinical treatment. .
传统的细胞毒性疗法对滑膜肉瘤的疗效有限，目前尚无专门针对致病 SS18-SSX 融合癌蛋白的药物。先前的研究表明，组蛋白去乙酰化酶（HDAC）抑制可破坏滑膜肉瘤致癌蛋白复合物，导致细胞凋亡。为了了解 HDAC 抑制的分子作用，对六个人滑膜肉瘤细胞系进行了 RNA-seq 转录组分析。HDAC 抑制诱导细胞周期停滞、神经元分化和对含氧物质反应的途径，这在其他用此类药物治疗的癌症中也观察到。更具体地说，多梳组靶标被重新激活，包括肿瘤抑制因子，诱导促凋亡转录模式。功能分析表明，ROS 介导的 FOXO 激活和促凋亡因子 BIK、BIM 和 BMF 对滑膜肉瘤中 HDAC 抑制诱导的细胞凋亡很重要。在滑膜肉瘤的小鼠模型中，经过 7 天的 quisinostat 治疗，HDAC 抑制剂通路的激活导致细胞凋亡和肿瘤负担减少。这项研究为滑膜肉瘤对 HDAC 抑制的特殊易感性提供了机制支持，作为临床治疗的一种手段。
