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Hypermethylation and global remodeling of DNA methylation associated with acquired cisplatin resistance in testicular germ cell tumors

ABSTRACT: Testicular germ cell tumors (TGCTs) are hypersensitive to cisplatin-based therapy however cisplatin resistance and poor outcomes do occur in a significant number of patients. It has been suggested that a shift toward DNA hypermethylation mediates cisplatin resistance in TGCT cells, although there is little direct evidence to support this claim. Here we utilized a series of isogenic cisplatin resistant cell models and observed a strong association between cisplatin resistance in TGCTs cells and a net increase in global CpG and non-CpG DNA methylation spanning regulatory, intergenic, genic and repeat elements. Hypermethylated loci were significantly enriched for repressive DNA segments, CTCF and RAD21 sites and lamina associated domains, suggesting that global nuclear reorganization of chromatin structure occurred in resistant cells. Hypomethylated CpG loci were significantly enriched for EZH2 and SUZ12 binding and H3K27me3 sites. Integrative transcriptome and methylome analysis showed a strong negative correlation between gene promoter CpG island methylation and gene expression in resistant cells and a weaker positive correlation between gene body methylation and gene expression. A bidirectional shift between gene promoter and gene body DNA methylation occurred within multiple genes that was associate with upregulation of polycomb targets and downregulation of tumor suppressor genes. These data support the hypothesis that global remodeling of DNA methylation is a key factor in mediating cisplatin hypersensitivity and chemoresistance of TGCTs and furthers the rationale for hypomethylation therapy for refractory TGCT patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156512 | GEO | 2020/12/25

REPOSITORIES: GEO

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Project description:The development of chemo-resistance has dramatically limited the clinical efficiency of platinum-based therapy. Although many resistant mechanisms have been demonstrated, genetic/molecular alterations responsible for drug resistance in the majority of clinical cases has not been identified. We analyzed three pairs of testicular germ cell tumor (TGCT) cell lines using Affymetrix expression microarrays to identify differential expressed genes. Then the expression of CCND1/CyclinD1, selected from the microarray analysis, was determined in cisplatin sensitive and resistance cancer samples including TGCTs, ovarian and prostate cancers by quantitative reverse transcription PCR analysis (qRT-PCR). Finally, we determined the gene knocked-down effect of CyclinD1. Expression microarray study revealed a limited number of differentially expressed genes across all three cell lines when comparing the parental and resistant cells. Among them, CyclinD1 was the most significantly differentially expressed gene. Importantly, we found that, in clinical TGCT samples, the overall expression level of cyclinD1 is higher in resistant cases compared to those sensitive samples (9/12 in the resistant group and only 3/8 in the sensitive group). We also found that cyclinD1 expressed dozens of fold higher in the resistant than in the sensitive ovarian cancer cell lines and dramatically overexpressed in prostate cancer. We re-sensitized the resistant cells by knocking-down cyclinD1. We demonstrated that deregulation of cyclinD1 is the major cause of TGCT cisplatin resistance and it may also be commonly involved in other human cancers. Combined cyclinD1 inhibition and cisplatin chemotherapy may be used clinically to treat the large number of cyclinD1 deregulated resistant tumors. RNA from three paired parental and cisplatin-resistant TGCT cell lines was extracted and analysed by Affymetrix gene expression microarray profiling (Human Genome U133 plus 2.0 arrays). Expression changes associated with the resistant phenotype were identified by comparing the three cisplatin-resistant derivatives to their parental counterparts.

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Hypermethylation and global remodeling of DNA methylation associated with acquired cisplatin resistance in testicular germ cell tumors

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