Involvement of enhancer of zeste homolog 2 in cisplatin-resistance in ovarian cancer cells by interacting with several genes

Abstract

In the present study, gene expression profiles of cisplatin-sensitive ovarian cancer (OC) cells were compared with those of cisplatin-resistant OC cells to identify key genes and pathways contributing to cisplatin resistance in ovarian cancer cells. The GSE15372 gene expression data set was downloaded from Gene Expression Omnibus, and included five biological replicates of cisplatin-sensitive OC cells and five biological replicates of cisplatin-resistant OC cells. Differentially expressed genes (DEGs) were screened using the limma package in R, based on the cut-off values of P<0.05 and |log2 (fold change)|>1. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and Gene Ontology enrichment analysis were performed on the DEGs using the Database for Annotation, Visualization and Integration Discovery. The protein-protein interaction (PPI) network was constructed for the DEGs using STRING, and sub-networks were analyzed by Clustering with Overlapping Neighborhood Expansion. A total of 556 DEGs were identified in the cisplatin-sensitive OC cells, of which 246 were upregulated and 310 were downregulated. Functional enrichment analysis revealed metabolism-associated pathways, DNA replication and cell cycle were significantly enriched in the downregulated genes, while cell growth and differentiation, response to stimulus, and apoptosis were significantly enriched in the upregulated genes. A PPI network, including 342 nodes was constructed for the DEGs and four subnetworks were extracted from the entire network. A total of 34 DEGs interacting with enhancer of zeste homolog 2 (EZH2) were identified, which were associated with DNA replication, pyrimidine metabolism and cell cycle. In conclusion, a number of key genes and pathways associated with the cisplatin-resistance of OC were revealed, particularly EZH2. These findings assist in the development of therapy for OC.

Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

“…In addition to mediating cellular platinum uptake, EZH2 participated in malignant biological behavior of ovarian cancer through regulating BRCA1 expression and enhanced cDDP resistance through promoting DNA replication, pyrimidine metabolism, cell cycle, and cell proliferation . Therefore, alteration of EZH2 regulating miRNAs and lncRNAs were also engaged in cDDP resistance .…”

Histone Methyltransferase EZH2: A Therapeutic Target for Ovarian Cancer

“…This highlights the importance of investigating the resistance pathways to first-line ovarian cancer treatment. Studies have shown that the overexpression of EZH2 contributes to acquired cisplatin resistance in ovarian cancer cells, while downregulation of EZH2 is found in cisplatin-sensitive cells (32,33). EZH2 has been shown to epigenetically silence tumor suppressor genes, such as ARNTL and hMLH1, which may contribute to chemoresistance in these tumors (34,35).…”

“…Wang et al looked at the interaction of EZH2 with several differentially expressed genes (DEGs) in cisplatin-resistant human ovarian cancer cells (CP70 cell line). They found that cell cycle, DNA replication and pyrimidine metabolism were significantly enriched in the DEGs that directly interacted with EZH2 (33). Another mechanism by which EZH2 confers resistance is by physical alteration of DNA.…”

EZH2-mediated repression of GSK-3β and TP53 promotes Wnt/β-catenin signaling-dependent cell expansion in cervical carcinoma

“…EZH2 regulates several cellular processes, including cell fate determination, cell cycle regulation, senescence, cell differentiation and carcinogenesis [9]. Furthermore, EZH2 has been reported to be overexpressed and to function as an oncogene in various cancers by mediating the expression of target genes involved in tumorigenesis [9, 10], including prostate cancer [11], breast cancer [12, 13], hepatocellular carcinoma [14], colorectal cancer [15, 16], gastric cancer [17], ovarian cancer [18], melanoma [19] and cervical cancer [20–23], suggesting the potential role of EZH2 in tumor. Additionally, EZH2 has been found to act as an epigenetic modifier during the TGF-β-induced epithelial-mesenchymal transition (EMT) in breast carcinogenesis and to control the p38 mitogen-activated protein kinase (MAPK) signaling pathway during breast cancer cell migration, invasion and metastasis [24].…”