RRC ID 65946
Author Oyama Y, Shigeta S, Tokunaga H, Tsuji K, Ishibashi M, Shibuya Y, Shimada M, Yasuda J, Yaegashi N.
Title CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents.
Journal PLoS One
Abstract Platinum sensitivity is an important prognostic factor in patients with ovarian cancer. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core member of the nucleosome remodeling and deacetylase complex, which functions as a chromatin remodeler. Emerging evidence indicates that CHD4 could be a potential therapeutic target for cancer therapy. The purpose of this study was to clarify the role of CHD4 in ovarian cancer and investigate its therapeutic potential focusing on platinum sensitivity. In an analysis of the Cancer Genome Atlas ovarian cancer dataset, CHD4 gene amplification was associated with worse overall survival. CHD4 mRNA expression was significantly higher in platinum-resistant samples in a subsequent clinical sample analysis, suggesting that CHD4 overexpression conferred platinum resistance to ovarian cancer cells, resulting in poor patient survival. In concordance with these findings, CHD4 knockdown enhanced the induction of apoptosis mediated by cisplatin in ovarian cancer cells TOV21G and increased cisplatin sensitivity in multiple ovarian cancer cells derived from different subtypes. However, CHD4 knockdown did not affect the expression of RAD51 or p21, the known targets of CHD4 in other cancer types that can modulate platinum sensitivity. Knockdown and overexpression assays revealed that CHD4 positively regulated the expression of multi-drug transporter MDR1 and its coding protein p-glycoprotein. In addition, a first-in-class CHD4/SMARCA5 inhibitor ED2-AD101 showed synergistic interactions with cisplatin. Our findings suggest that CHD4 mediates platinum sensitivity by modulating MDR1 expression in ovarian cancer. Further, CHD4 suppression has a potential to be a novel therapeutic strategy in combination with platinum agents.
Volume 16(6)
Pages e0251079
Published 2021-1-1
DOI 10.1371/journal.pone.0251079
PII PONE-D-20-33496
PMID 34161330
PMC PMC8221472
MeSH ATP Binding Cassette Transporter, Subfamily B / genetics Antineoplastic Agents / therapeutic use* Apoptosis / drug effects Apoptosis / genetics Carcinoma, Ovarian Epithelial / drug therapy Carcinoma, Ovarian Epithelial / genetics Carcinoma, Ovarian Epithelial / pathology Cell Line, Tumor Cell Movement / drug effects Cell Movement / genetics Cell Proliferation / drug effects Cell Proliferation / genetics Chromatin Assembly and Disassembly / drug effects Chromatin Assembly and Disassembly / genetics Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / genetics Female Gene Expression Regulation, Neoplastic / genetics Humans Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics* Organoplatinum Compounds / therapeutic use* Ovarian Neoplasms / drug therapy* Ovarian Neoplasms / genetics* Ovarian Neoplasms / pathology
IF 2.74
Human and Animal Cells JHOS-2(RCB1521) JHOC-5(RCB1520)