EZH2 inhibition sensitizes retinoic acid-driven senescence in Synovial sarcoma

Abstract Synovial sarcoma (SS) is driven by a unique chromosomal translocation t(18;X) leading to expression of the SS18-SSXfusion oncoprotein, a transcriptional regulator with both activating and repressing functions. Here we investigated the role of PRAME (Preferentially Expressed Antigen in Melanoma), a protein highly expressed in SS but with a poorly understood function. PRAME is a repressor of retinoic acid (RA) signaling, forming a complex with RA-receptor (RAR) and Enhancer of Zeste Homolog 2 (EZH2). In silico analyses show that expression of PRAME is associated with suppression of RA signaling in SS. The SS18-SSX fusion protein directly targets the PRAME promoter and expression of SS18-SSX and PRAME are positively correlated. As there are no pharmacological inhibitors against PRAME, we used GSK343 for inhibition of EZH2 in combination with all- trans retinoic acid (ATRA) to reconstitute RA signaling. PRAME formed complexes with EZH2 and RAR, while exposure to GSK343 disrupted the PRAME-EZH2 interaction. Combination treatment with GSK343 and ATRA decreased cell proliferation and resulted in cellular senescence. Knockdown of PRAME suppressed the response to ATRA treatment in SS. Our data connect SS18-SSX with RA signaling and the EZH2 complex, providing insights into how this fusion oncoprotein disrupts normal cellular homeostasis.