crc-22-0518-s04.pdf (186.92 kB)
Supplementary Figure S3 from Targeting the clear cell sarcoma oncogenic driver fusion gene EWSR1:ATF1 by HDAC inhibition
journal contributionposted on 2023-06-08, 13:40 authored by Hirokazu Mae, Hidetatsu Outani, Yoshinori Imura, Ryota Chijimatsu, Akitomo Inoue, Yuki Kotani, Naohiro Yasuda, Sho Nakai, Takaaki Nakai, Satoshi Takenaka, Seiji Okada
Fig. S3 Mivebresib (ABBV-075) inhibited cell viability of CCS cells and lowered expression of EWSR1::ATF1.
ARTICLE ABSTRACTClear cell sarcoma (CCS), a rare but extremely aggressive malignancy with no effective therapy, is characterized by the expression of the oncogenic driver fusion gene EWSR1::ATF1. 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 EWSR1::ATF1. We expected the reduced expression of EWSR1::ATF1 to be due to the alteration of chromatin accessibility; however, ATAC sequencing and a CUT&RUN 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 q-PCR analyses. In addition, motif analysis revealed that vorinostat treatment suppressed the transcriptional factor SOX10, which directly regulates EWSR1::ATF1 expression and is involved in CCS proliferation. Importantly, we demonstrate that a combination therapy of vorinostat and JQ1 synergistically enhances antiproliferation effect and EWSR1::ATF1 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.