Abstract
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.
Highlights
Synovial sarcoma is an aggressive soft tissue malignancy that primarily affects adolescents and young adults [1]
The SS18-SSX fusion oncoprotein has been proposed to interact in place of native SS18, leading to aberrant SWI/SNF–mediated transcription [3], and to act as a nidus for abnormal assembly of polycomb group members (PcG) and transcription factors that lead to transcriptional repression by EZH2-mediated H3K27 trimethylation [4]
Expression of tumor suppressor genes EGR1 and CDKN2A has been shown to be directly repressed by SS18-SSX, whereas the antiapoptotic protein BCL2 is characteristically upregulated [5] leading to a proliferative and antiapoptotic phenotype
Summary
Synovial sarcoma is an aggressive soft tissue malignancy that primarily affects adolescents and young adults [1]. It is characterized by the driving chimeric oncoprotein SS18-SSX, derived from the t(X;18)(p11.2;q11.2) translocation [2]. The SS18-SSX fusion oncoprotein has been proposed to interact in place of native SS18, leading to aberrant SWI/SNF–mediated transcription [3], and to act as a nidus for abnormal assembly of polycomb group members (PcG) and transcription factors that lead to transcriptional repression by EZH2-mediated H3K27 trimethylation [4]. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Expression of tumor suppressor genes EGR1 and CDKN2A has been shown to be directly repressed by SS18-SSX, whereas the antiapoptotic protein BCL2 is characteristically upregulated [5] leading to a proliferative and antiapoptotic phenotype.
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