Data from Targeting the Clear Cell Sarcoma Oncogenic Driver Fusion Gene <i>EWSR1::ATF1</i> by HDAC Inhibition

<div><p>Clear cell sarcoma (CCS), a rare but extremely aggressive malignancy with no effective therapy, is characterized by the expression of the oncogenic driver fusion gene <i>EWSR1::ATF1</i>. In this study, we performed a high-throughput drug screening, finding that the histone deacetylase inhibitor vorinostat exerted an antiproliferation effect with the reduced expression of <i>EWSR1::ATF1</i>. We expected the reduced expression of <i>EWSR1::ATF1</i> to be due to the alteration of chromatin accessibility; however, assay for transposase-accessible chromatin using sequencing and a cleavage under targets and release using nuclease assay revealed that chromatin structure was only slightly altered, despite histone deacetylation at the EWSR1::ATF1 promoter region. Alternatively, we found that vorinostat treatment reduced the level of BRD4, a member of the bromodomain and extraterminal motif protein family, at the EWSR1::ATF1 promoter region. Furthermore, the BRD4 inhibitor JQ1 downregulated EWSR1::ATF1 according to Western blotting and qPCR analyses. In addition, motif analysis revealed that vorinostat treatment suppressed the transcriptional factor SOX10, which directly regulates <i>EWSR1::ATF1</i> expression and is involved in CCS proliferation. Importantly, we demonstrate that a combination therapy of vorinostat and JQ1 synergistically enhances antiproliferation effect and <i>EWSR1::ATF1</i> suppression. These results highlight a novel fusion gene suppression mechanism achieved using epigenetic modification agents and provide a potential therapeutic target for fusion gene–related tumors.</p>Significance:<p>This study reveals the epigenetic and transcriptional suppression mechanism of the fusion oncogene <i>EWSR1::ATF1</i> in clear cell sarcoma by histone deacetylase inhibitor treatment as well as identifying SOX10 as a transcription factor that regulates <i>EWSR1::ATF1</i> expression.</p></div>