EZH2-regulated PARP-1 Expression is a Likely Mechanism for the Chemoresistance of Gliomas to Temozolomide
Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net..
BACKGROUND: Chemoresistance in gliomas accounts for the major cause of tumor progress and recurrence during comprehensive treatment with alkylating agents including temozolomide (TMZ). The oncogenic role of Enhancer of zeste homolog 2 (EZH2) has been identified in many solid malignancies including gliomas, though the accurate effect of EZH2 on chemotherapy resistance of gliomas has been elusive.
OBJECTIVE: To elucidate the role of EHZ2 on TMZ resistance of gliomas and the molecular mechanisms.
METHODS: Immunohistochemistry (IHC) and Reverse transcription-quantitative (RT-q) PCR, and western blot assay were performed for expressional analysis. Cell Counting Kit-8 (CCK-8) assay was applied to determine the TMZ sensitivity. EZH2-silencing lentivirus was generated for mechanic study.
RESULTS: EZH2 was overexpressed in gliomas both at the transcriptional and protein levels. EZH2 level in glioma cell lines was positively correlated with resistance to TMZ, represented by the 50% inhibition rate (IC50). Moreover, there was increased TMZ sensitivity in EZH2-inhibited glioma cells than in the control cells. Furthermore, we determined that PARP1 was a common molecule among the downregulated DNA repair proteins in both U251 and U87 glioma cell lines after EZH2 inhibition. Specifically, we observed a spontaneous increase of PARP1 expression with TMZ treatment and interestingly, the increase of PARP1 could be also reduced by EZH2 inhibition in the glioma cells. Finally, combined treatment with lentivirus-induced EZH2 inhibition and a PARP1 inhibitor dramatically enhanced TMZ cytotoxicity compared with either one alone.
CONCLUSION: EZH2-PARP-1 signaling axis is possibly responsible for the chemoresistance of gliomas to TMZ. Simultaneously inhibiting these two genes may improve the outcome of TMZ chemotherapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Current cancer drug targets - 24(2024), 3 vom: 01., Seite 328-339 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liang, Qiang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.04.2024 Date Revised 05.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.2174/1568009623666230818151830 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a published: Print | ||
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| 520 | |a Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net. | ||
| 520 | |a BACKGROUND: Chemoresistance in gliomas accounts for the major cause of tumor progress and recurrence during comprehensive treatment with alkylating agents including temozolomide (TMZ). The oncogenic role of Enhancer of zeste homolog 2 (EZH2) has been identified in many solid malignancies including gliomas, though the accurate effect of EZH2 on chemotherapy resistance of gliomas has been elusive | ||
| 520 | |a OBJECTIVE: To elucidate the role of EHZ2 on TMZ resistance of gliomas and the molecular mechanisms | ||
| 520 | |a METHODS: Immunohistochemistry (IHC) and Reverse transcription-quantitative (RT-q) PCR, and western blot assay were performed for expressional analysis. Cell Counting Kit-8 (CCK-8) assay was applied to determine the TMZ sensitivity. EZH2-silencing lentivirus was generated for mechanic study | ||
| 520 | |a RESULTS: EZH2 was overexpressed in gliomas both at the transcriptional and protein levels. EZH2 level in glioma cell lines was positively correlated with resistance to TMZ, represented by the 50% inhibition rate (IC50). Moreover, there was increased TMZ sensitivity in EZH2-inhibited glioma cells than in the control cells. Furthermore, we determined that PARP1 was a common molecule among the downregulated DNA repair proteins in both U251 and U87 glioma cell lines after EZH2 inhibition. Specifically, we observed a spontaneous increase of PARP1 expression with TMZ treatment and interestingly, the increase of PARP1 could be also reduced by EZH2 inhibition in the glioma cells. Finally, combined treatment with lentivirus-induced EZH2 inhibition and a PARP1 inhibitor dramatically enhanced TMZ cytotoxicity compared with either one alone | ||
| 520 | |a CONCLUSION: EZH2-PARP-1 signaling axis is possibly responsible for the chemoresistance of gliomas to TMZ. Simultaneously inhibiting these two genes may improve the outcome of TMZ chemotherapy | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Wang, Junyu |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Jing |e verfasserin |4 aut | |
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