ATF1 by HDAC Inhibition
© 2023 The Authors; Published by the American Association for Cancer Research..
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, 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 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.
ATF1 in clear cell sarcoma by histone deacetylase inhibitor treatment as well as identifying SOX10 as a transcription factor that regulates EWSR1::ATF1 expression.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:3 |
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| Enthalten in: |
Cancer research communications - 3(2023), 7 vom: 30. Juli, Seite 1152-1165 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mae, Hirokazu [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.07.2023 Date Revised 18.07.2023 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1158/2767-9764.CRC-22-0518 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359062873 |
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| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Mae, Hirokazu |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Targeting the Clear Cell Sarcoma Oncogenic Driver Fusion Gene EWSR1::ATF1 by HDAC Inhibition |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.07.2023 | ||
| 500 | |a Date Revised 18.07.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a 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 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, 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 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 | ||
| 520 | |a Significance: This study reveals the epigenetic and transcriptional suppression mechanism of the fusion oncogene EWSR1::ATF1 in clear cell sarcoma by histone deacetylase inhibitor treatment as well as identifying SOX10 as a transcription factor that regulates EWSR1::ATF1 expression | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a Histone Deacetylase Inhibitors |2 NLM | |
| 650 | 7 | |a Vorinostat |2 NLM | |
| 650 | 7 | |a 58IFB293JI |2 NLM | |
| 650 | 7 | |a BRD4 protein, human |2 NLM | |
| 650 | 7 | |a Cell Cycle Proteins |2 NLM | |
| 650 | 7 | |a EWSR1 protein, human |2 NLM | |
| 650 | 7 | |a RNA-Binding Protein EWS |2 NLM | |
| 700 | 1 | |a Outani, Hidetatsu |e verfasserin |4 aut | |
| 700 | 1 | |a Imura, Yoshinori |e verfasserin |4 aut | |
| 700 | 1 | |a Chijimatsu, Ryota |e verfasserin |4 aut | |
| 700 | 1 | |a Inoue, Akitomo |e verfasserin |4 aut | |
| 700 | 1 | |a Kotani, Yuki |e verfasserin |4 aut | |
| 700 | 1 | |a Yasuda, Naohiro |e verfasserin |4 aut | |
| 700 | 1 | |a Nakai, Sho |e verfasserin |4 aut | |
| 700 | 1 | |a Nakai, Takaaki |e verfasserin |4 aut | |
| 700 | 1 | |a Takenaka, Satoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Okada, Seiji |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cancer research communications |d 2021 |g 3(2023), 7 vom: 30. Juli, Seite 1152-1165 |w (DE-627)NLM334868343 |x 2767-9764 |7 nnns |
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