Human synovial sarcoma: towards novel therapeutic strategies

Abstract

Synovial sarcomas are aggressive soft-tissue tumors, accounting for w10% of all human sarcomas. In over 95% of all cases, the SS18 gene is fused to either one of three highly homologous SSX genes (SSX1, SSX2, or SSX4). This fusion gene encodes an in-frame SS18eSSX fusion protein, which induces malignant transformation. Previous research has demonstrated that the wild-type SS18, and the SS18eSSX fusion proteins are components of the BRG1-associated (BAF) protein complex, which is involved in chromatin remodeling and transcriptional activation. Since wild-type SSX proteins act as transcriptional repressors, the SSX moiety is expected to hamper the normal SS18-associated functions within this BAF complex. In line with this notion, we have provided evidence that the SS18eSSX fusion proteins act as ‘activator-repressors’ of transcription, and we have shown that the deregulation of SS18eSSX target genes occurs through epigenetic mechanisms at the level of histone modifications. Interestingly, ‘epigenetic’ drugs such as histone de-acetylase (HDAC) inhibitors exhibit a remarkable efficacy on synovial sarcomas. Despite the undeniable therapeutic promise of HDAC inhibitors, the molecular mechanisms behind these treatment modalities remain elusive. Since these compounds elicit a wide range of cellular effects, we aim to unravel the molecular basis of the HDAC inhibitor sensitivity of synovial sarcomas by genetic means. The human genome contains eleven different HDACs, grouped in four classes according to their protein composition and substrate specificity. First, we analyzed which HDACs are expressed in synovial sarcomas, then we used small interfering RNA’s to down-regulate individual HDACs in synovial sarcoma cells. Finally, we combined this HDAC knockdown with HDAC inhibitor treatment and analysed its effects on cellular growth and viability. Our data show that synovial sarcoma cells mainly express one class of HDACs. Specific knockdown of these HDACs induces a significant decrease of synovial sarcoma cell growth and viability. Surprisingly, we found that HDAC knockdown sensitizes synovial sarcoma cells to HDAC inhibitor treatment. To address this latter response, we employed expression profiling to identify the signalling pathways which are affected by this treatment. Ultimately, this work may provide a rationale for the development of more specifically targeted therapies for this aggressive soft tissue tumor. EVOLUTION OF THE CANCER GENOME