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ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression
BACKGROUND: Resistance to platinum-based chemotherapy is a major cause of therapeutic failure during the treatment of epithelial ovarian cancer (EOC) patients. Our study aims to elucidate the molecular mechanisms by which ZNF711 down regulation promotes CISPLATIN resistance in EOC. METHODS: ZNF711 e...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441092/ https://www.ncbi.nlm.nih.gov/pubmed/34521054 http://dx.doi.org/10.1016/j.ebiom.2021.103558 |
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author | Wu, Geyan Peng, Hu Tang, Miaoling Yang, Meisongzhu Wang, Jun Hu, Yameng Li, Ziwen Li, Jun Li, Zheng Song, Libing |
author_facet | Wu, Geyan Peng, Hu Tang, Miaoling Yang, Meisongzhu Wang, Jun Hu, Yameng Li, Ziwen Li, Jun Li, Zheng Song, Libing |
author_sort | Wu, Geyan |
collection | PubMed |
description | BACKGROUND: Resistance to platinum-based chemotherapy is a major cause of therapeutic failure during the treatment of epithelial ovarian cancer (EOC) patients. Our study aims to elucidate the molecular mechanisms by which ZNF711 down regulation promotes CISPLATIN resistance in EOC. METHODS: ZNF711 expression in 150 EOC specimens was examined using immunohistochemistry. ZNF711 expression and the survival of EOC patients were assessed with a Kaplan-Meier analysis. The effects of ZNF711 expression on CDDP resistance were studied by IC50, Annexin V, and colony formation in vitro, and in an in vivo intra-peritoneal tumor model. The molecular mechanism was determined using a luciferase reporter assay, ChIP assay, CAPTURE approach, and co-IP assay. FINDINGS: ZNF711 down-regulation exerts a great impact on CDDP resistance for EOC patients by suppressing SLC31A1 and inhibiting CDDP influx. ZNF711 down-regulation promoted, while ZNF711 overexpression drastically inhibited CDDP resistance, both in vivo and in vitro. Mechanistically, the histone demethylase JHDM2A was recruited to the SLC31A1 promoter by ZNF711 and decreased the H3K9me2 level, resulting in the activation of SLC31A1 transcription and enhancement of CDDP uptake. Importantly, co-treatment with the histone methylation inhibitor, BIX-01294, increased the therapeutic efficacy of CDDP treatment in ZNF711-suppressed EOC cells. INTERPRETATION: These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment. FUNDING: This work was supported by the Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities; and China Postdoctoral Science Foundation. |
format | Online Article Text |
id | pubmed-8441092 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-84410922021-09-17 ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression Wu, Geyan Peng, Hu Tang, Miaoling Yang, Meisongzhu Wang, Jun Hu, Yameng Li, Ziwen Li, Jun Li, Zheng Song, Libing EBioMedicine Research paper BACKGROUND: Resistance to platinum-based chemotherapy is a major cause of therapeutic failure during the treatment of epithelial ovarian cancer (EOC) patients. Our study aims to elucidate the molecular mechanisms by which ZNF711 down regulation promotes CISPLATIN resistance in EOC. METHODS: ZNF711 expression in 150 EOC specimens was examined using immunohistochemistry. ZNF711 expression and the survival of EOC patients were assessed with a Kaplan-Meier analysis. The effects of ZNF711 expression on CDDP resistance were studied by IC50, Annexin V, and colony formation in vitro, and in an in vivo intra-peritoneal tumor model. The molecular mechanism was determined using a luciferase reporter assay, ChIP assay, CAPTURE approach, and co-IP assay. FINDINGS: ZNF711 down-regulation exerts a great impact on CDDP resistance for EOC patients by suppressing SLC31A1 and inhibiting CDDP influx. ZNF711 down-regulation promoted, while ZNF711 overexpression drastically inhibited CDDP resistance, both in vivo and in vitro. Mechanistically, the histone demethylase JHDM2A was recruited to the SLC31A1 promoter by ZNF711 and decreased the H3K9me2 level, resulting in the activation of SLC31A1 transcription and enhancement of CDDP uptake. Importantly, co-treatment with the histone methylation inhibitor, BIX-01294, increased the therapeutic efficacy of CDDP treatment in ZNF711-suppressed EOC cells. INTERPRETATION: These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment. FUNDING: This work was supported by the Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities; and China Postdoctoral Science Foundation. Elsevier 2021-09-11 /pmc/articles/PMC8441092/ /pubmed/34521054 http://dx.doi.org/10.1016/j.ebiom.2021.103558 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research paper Wu, Geyan Peng, Hu Tang, Miaoling Yang, Meisongzhu Wang, Jun Hu, Yameng Li, Ziwen Li, Jun Li, Zheng Song, Libing ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression |
title | ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression |
title_full | ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression |
title_fullStr | ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression |
title_full_unstemmed | ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression |
title_short | ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression |
title_sort | znf711 down-regulation promotes cisplatin resistance in epithelial ovarian cancer via interacting with jhdm2a and suppressing slc31a1 expression |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441092/ https://www.ncbi.nlm.nih.gov/pubmed/34521054 http://dx.doi.org/10.1016/j.ebiom.2021.103558 |
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