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 CDKN2A, 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 Ptenfl/fl;hSS2 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. Mol Cancer Ther; 16(12); 2656–67. ©2017 AACR.

中文翻译：

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HDAC抑制导致滑膜肉瘤细胞死亡

滑膜肉瘤的常规细胞毒性疗法提供的益处有限，目前还没有专门针对致病 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) 抑制会破坏滑膜肉瘤癌蛋白复合物，导致细胞凋亡。为了了解 HDAC 抑制的分子效应，在六种人类滑膜肉瘤细胞系中进行了 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的反应途径，在用此类药物治疗的其他癌症中也观察到了影响。更具体地针对滑膜肉瘤，polycomb 组靶点被重新激活，包括肿瘤抑制因子 CDKN2A，并诱导了促凋亡转录模式。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 抑制后的凋亡诱导很重要。在 Ptenfl/fl;hSS2 滑膜肉瘤小鼠模型中，经过 7 天 quisinostat 治疗后，HDAC 抑制剂途径激活导致细胞凋亡并减少肿瘤负荷。这项研究为滑膜肉瘤对 HDAC 抑制作为临床治疗手段的特殊敏感性提供了机制支持。摩尔癌症治疗; 16(12); 2656-67。©2017 AACR。在 Ptenfl/fl;hSS2 滑膜肉瘤小鼠模型中接受 7 天 quisinostat 治疗后，HDAC 抑制剂途径激活导致细胞凋亡并减少肿瘤负荷。这项研究为滑膜肉瘤对 HDAC 抑制作为临床治疗手段的特殊敏感性提供了机制支持。摩尔癌症治疗; 16(12); 2656-67。©2017 AACR。在 Ptenfl/fl;hSS2 滑膜肉瘤小鼠模型中接受 7 天 quisinostat 治疗后，HDAC 抑制剂途径激活导致细胞凋亡并减少肿瘤负荷。这项研究为滑膜肉瘤对 HDAC 抑制作为临床治疗手段的特殊敏感性提供了机制支持。摩尔癌症治疗; 16(12); 2656-67。©2017 AACR。