ZNF711 down-regulation promotes CISPLATIN resistance in epithelial ovarian cancer via interacting with JHDM2A and suppressing SLC31A1 expression.
Animals
Antineoplastic Agents
/ therapeutic use
Carcinoma
/ drug therapy
Cell Line, Tumor
Cisplatin
/ therapeutic use
Copper Transporter 1
/ genetics
DNA-Binding Proteins
/ genetics
Down-Regulation
Drug Resistance, Neoplasm
Female
Humans
Jumonji Domain-Containing Histone Demethylases
/ metabolism
Mice
Mice, Inbred BALB C
Ovarian Neoplasms
/ drug therapy
BIX-01294
Chemo resistance
Epithelial ovarian cancer
Histone methylation
ZNF711
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Sep 2021
Sep 2021
Historique:
received:
21
02
2021
revised:
10
08
2021
accepted:
13
08
2021
pubmed:
15
9
2021
medline:
28
1
2022
entrez:
14
9
2021
Statut:
ppublish
Résumé
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. 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. 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. These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment. 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.
Sections du résumé
BACKGROUND
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
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
RESULTS
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
CONCLUSIONS
These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment.
FUNDING
BACKGROUND
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.
Identifiants
pubmed: 34521054
pii: S2352-3964(21)00351-0
doi: 10.1016/j.ebiom.2021.103558
pmc: PMC8441092
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Copper Transporter 1
0
DNA-Binding Proteins
0
SLC31A1 protein, human
0
ZNF711 protein, human
0
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103558Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare no conflict of interest.