Therapeutic Potential of Bromodomain and Extra-Terminal Domain Inhibitors for Synovial Sarcoma Cells

Simple Summary Synovial sarcoma, a rare type of soft-tissue sarcoma, currently lacks efficacious anticancer therapies. This sarcoma is characterized by the SS18-SSX fusion gene, which plays a pivotal role in epigenetic regulation. Our study centered on epigenetic modulators, particularly bromodomain and extra-terminal domain (BET) inhibitors. Bromodomains are "readers" of histone modifications that facilitate the initiation and elongation of gene transcription. BET inhibitors are known to obstruct bromodomain binding, thereby attenuating the expression of tumor-associated genes. This study demonstrates that BET inhibitors modulate cell-cycle regulators and members of the BCL2 family in synovial sarcoma, resulting in cell-cycle arrest and apoptosis. Furthermore, we observed that silencing SS18-SSX diminishes BCL2 expression and reduces sensitivity to BET inhibitors. Our findings indicate that BET inhibitors may effectively target the intrinsic apoptotic pathway modulated by SS18-SSX in synovial sarcoma, suggesting that BET inhibitors could represent a promising therapeutic approach for this malignancy.Abstract Synovial sarcoma (SS), a rare subtype of soft-tissue sarcoma distinguished by expression of the fusion gene SS18-SSX, predominantly affects the extremities of young patients. Existing anticancer drugs have limited efficacy against this malignancy, necessitating the development of innovative therapeutic approaches. Given the established role of SS18-SSX in epigenetic regulation, we focused on bromodomain and extra-terminal domain protein (BET) inhibitors and epigenetic agents. Our investigation of the BET inhibitor ABBV-075 revealed its pronounced antitumor effects, inducing G1-phase cell-cycle arrest and apoptosis, in four SS cell lines. Notably, BET inhibitors exhibited regulatory control over crucial cell-cycle regulators, such as MYC, p21, CDK4, and CDK6. Additionally, RNA sequencing findings across the four cell lines revealed the significance of fluctuating BCL2 family protein expression during apoptotic induction. Notably, variations in the expression ratio of the anti-apoptotic factor BCLxL and the pro-apoptotic factor BIM may underlie susceptibility to ABBV-075. Additionally, knockdown of SS18-SSX, which upregulates BCL2, reduced the sensitivity to ABBV-075. These findings suggest the potential utility of BET inhibitors targeting the SS18-SSX-regulated intrinsic apoptotic pathway as a promising therapeutic strategy for SS.