EPIC-0628 abrogates HOTAIR/EZH2 interaction and enhances the temozolomide efficacy via promoting ATF3 expression and inhibiting DNA damage repair in glioblastoma
Copyright © 2024. Published by Elsevier B.V..
The efficacy of temozolomide (TMZ) treatment in glioblastoma (GBM) is influenced by various mechanisms, mainly including the level of O6-methylguanine-DNA methyltransferase (MGMT) and the activity of DNA damage repair (DDR) pathways. In our previous study, we had proved that long non-coding RNA HOTAIR regulated the GBM progression and mediated DDR by interacting with EZH2, the catalytic subunit of PRC2. In this study, we developed a small-molecule inhibitor called EPIC-0628 that selectively disrupted the HOTAIR-EZH2 interaction and promoted ATF3 expression. The upregulation of ATF3 inhibited the recruitment of p300, p-p65, p-Stat3 and SP1 to the MGMT promoter. Hence, EPIC-0628 silenced MGMT expression. Besides, EPIC-0628 induced cell cycle arrest by increasing the expression of CDKN1A and impaired DNA double-strand break repair via suppressing the ATF3-p38-E2F1 pathway. Lastly, EPIC-0628 enhanced TMZ efficacy in GBM in vitro and vivo. Hence, this study provided evidence for the combination of epigenetic drugs EPIC-0628 with TMZ for GBM treatment through the above mechanisms.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:588 |
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| Enthalten in: |
Cancer letters - 588(2024) vom: 28. Apr., Seite 216812 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Eryan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 09.04.2024 Date Revised 09.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.canlet.2024.216812 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a EPIC-0628 abrogates HOTAIR/EZH2 interaction and enhances the temozolomide efficacy via promoting ATF3 expression and inhibiting DNA damage repair in glioblastoma |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024. Published by Elsevier B.V. | ||
| 520 | |a The efficacy of temozolomide (TMZ) treatment in glioblastoma (GBM) is influenced by various mechanisms, mainly including the level of O6-methylguanine-DNA methyltransferase (MGMT) and the activity of DNA damage repair (DDR) pathways. In our previous study, we had proved that long non-coding RNA HOTAIR regulated the GBM progression and mediated DDR by interacting with EZH2, the catalytic subunit of PRC2. In this study, we developed a small-molecule inhibitor called EPIC-0628 that selectively disrupted the HOTAIR-EZH2 interaction and promoted ATF3 expression. The upregulation of ATF3 inhibited the recruitment of p300, p-p65, p-Stat3 and SP1 to the MGMT promoter. Hence, EPIC-0628 silenced MGMT expression. Besides, EPIC-0628 induced cell cycle arrest by increasing the expression of CDKN1A and impaired DNA double-strand break repair via suppressing the ATF3-p38-E2F1 pathway. Lastly, EPIC-0628 enhanced TMZ efficacy in GBM in vitro and vivo. Hence, this study provided evidence for the combination of epigenetic drugs EPIC-0628 with TMZ for GBM treatment through the above mechanisms | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Glioblastoma | |
| 650 | 4 | |a HOTAIR | |
| 650 | 4 | |a Homologous recombination | |
| 650 | 4 | |a MGMT | |
| 650 | 4 | |a Temozolomide | |
| 650 | 7 | |a Temozolomide |2 NLM | |
| 650 | 7 | |a YF1K15M17Y |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents, Alkylating |2 NLM | |
| 650 | 7 | |a Dacarbazine |2 NLM | |
| 650 | 7 | |a 7GR28W0FJI |2 NLM | |
| 650 | 7 | |a DNA Repair Enzymes |2 NLM | |
| 650 | 7 | |a EC 6.5.1.- |2 NLM | |
| 650 | 7 | |a O(6)-Methylguanine-DNA Methyltransferase |2 NLM | |
| 650 | 7 | |a EC 2.1.1.63 |2 NLM | |
| 650 | 7 | |a DNA Modification Methylases |2 NLM | |
| 650 | 7 | |a EC 2.1.1.- |2 NLM | |
| 650 | 7 | |a EZH2 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.1.1.43 |2 NLM | |
| 650 | 7 | |a Enhancer of Zeste Homolog 2 Protein |2 NLM | |
| 650 | 7 | |a EC 2.1.1.43 |2 NLM | |
| 650 | 7 | |a ATF3 protein, human |2 NLM | |
| 650 | 7 | |a Activating Transcription Factor 3 |2 NLM | |
| 700 | 1 | |a Hong, Biao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yunfei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qixue |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jixing |e verfasserin |4 aut | |
| 700 | 1 | |a Cui, Xiaoteng |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Ye |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Shixue |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Dongyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xiaomin |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, Chunsheng |e verfasserin |4 aut | |
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