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Table S1 shows the cell viability inhibitory rate (%) in SCCOHT cell lines vs other cell lines in the epigenetic drug screen. Table S2 shows the effects of Quisinostat on the proteome of BIN67 cells after treatment for 24 or 72 hours. Table S3 shows the significantly altered proteins by Quisinostat treatment for 24 hours in BIN67 cells. Table S4 shows the significantly altered proteins by Quisinostat treatment for 72 hours in BIN67 cells. Table S5 shows the biological functions that were significantly affected by Quisinostat treatment for 72 hours in BIN67 cells. Table S6 shows the proteins that were significantly regulated by SMARCA4 re-expression in BIN67 cells. Table S7 shows the biological functions that were significantly affected by SMARCA4 re-expression in BIN67 cells. Table S8 shows the proteins that were significantly regulated by both Quisinostat treatment (72 hr) and SMARCA4 re-expression in BIN67 cells. Table S9 shows the biological functions that were significantly affected by both Quisinostat and SMARCA4 re-expression in BIN67 cells.

Fig.S1 shows that SCCOHT cells are sensitive to HDAC inhibition. Fig. S2 shows that SCCOHT cells are sensitive to HDAC inhibition or depletion. Fig.S3 shows that SMARCA4/A2 dual deficiency is not associated with hypersensitivity to HDAC inhibitors in lung and pancreatic cancer cell lines. Fig.S4 shows that pan-HDAC inhibitors induce cell morphology changes in SCCOHT cells. Fig.S5 shows that SMARCA2 activation is partially required for the hypersensitivity of SCCOHT cells to HDAC inhibition. Fig. S6 shows the effect of quisinostat on mouse body weights in BIN67 mouse xenograft models. Fig.S7 shows the synergistic effects between HDAC inhibitors and EZH2 inhibitors in SWI/SNF deficiency-driven tumor cells. Fig. S8 shows that depletion of HDAC2 increased sensitivity of BIN67 cells to EPZ-6438 treatment. Fig.S9 shows the synergistic effects between HDAC inhibitors and EZH2 inhibitors in SCCOHT cells. Fig.S10 shows the effect of combined treatment of EPZ-6438 and quisinostat on mouse body weight and survival.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but extremely lethal malignancy that mainly impacts young women. SCCOHT is characterized by a diploid genome with loss of SMARCA4 and lack of SMARCA2 expression, two mutually exclusive ATPases of the SWI/SNF chromatin-remodeling complex. We and others have identified the histone methyltransferase EZH2 as a promising therapeutic target for SCCOHT, suggesting that SCCOHT cells depend on the alternation of epigenetic pathways for survival. In this study, we found that SCCOHT cells were more sensitive to pan-HDAC inhibitors compared with other ovarian cancer lines or immortalized cell lines tested. Pan-HDAC inhibitors, such as quisinostat, reversed the expression of a group of proteins that were deregulated in SCCOHT cells due to SMARCA4 loss, leading to growth arrest, apoptosis, and differentiation in vitro and suppressed tumor growth of xenografted tumors of SCCOHT cells. Moreover, combined treatment of HDAC inhibitors and EZH2 inhibitors at sublethal doses synergistically induced histone H3K27 acetylation and target gene expression, leading to rapid induction of apoptosis and growth suppression of SCCOHT cells and xenografted tumors. Therefore, our preclinical study highlighted the therapeutic potential of combined treatment of HDAC inhibitors with EZH2 catalytic inhibitors to treat SCCOHT.