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An epigenomic approach to identifying differential overlapping and cis-acting lncRNAs in cisplatin-resistant cancer cells

ABSTRACT: Long noncoding RNAs are newly discovered regulators that play a critical role in cell biology, crucial to the correct functioning of the cell. Alterations in lncRNAs can lead to the development of diseases such as cancer. However, the role of lncRNAs in resistance to platinum chemotherapy is largely unknown. To screen for epigenetic changes involved in the development of resistance, we combined lncRNA and mRNA expression microarrays with whole genome bisulfite sequencing (WGBS) in four paired cisplatin-sensitive/resistant cells from non-small cell lung cancer and ovarian cancer. We found low levels of expression changes in lncRNAs (1.5%) and mRNAs (2%) when comparing resistant vs. sensitive cells. The correlation between lncRNA/mRNA arrays and WGBS identified two groups of lncRNAs, classified according to their relationship with the gene they have in silico complementarity or with their possible epigenetic regulation at the DNA methylation level. Validation of the results of expression and methylation levels allowed us to characterize lncRNAs in cisplatin-resistant phenotypes. In this study, we characterized lncRNAs that change in cisplatin-resistant cells due to epigenetic regulation at the DNA methylation level and the associated changes in expression levels. We have identified two groups of differentially expressed and methylated lncRNAs, indicating a new approach to the study of the mechanisms involved in the development of acquired resistance to cisplatin in cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108139 | GEO | 2018/06/14

REPOSITORIES: GEO

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Project description:Multiple DNA methylation changes have been associated with the acquisition of drug resistance; however it remains uncertain how many of these changes may represent critical DNA methylation drivers of chemoresistance. Using genome-wide DNA methylation profiling across 27,578 CpG sites on Illumina HumanMethylation27 bead array we identified loci at 4092 genes becoming hypermethylated in the chemoresistant A2780/cp70 ovarian tumour cell line compared to the parental sensitive A2780 line. Hypermethylation at CpG islands (CGI) is often associated with transcriptional silencing, however only 245 of these hypermethylated genes become down-regulated in A2780/cp70 as measured by microarray expression profiling. Treatment with the demethylating agent Decitabine induces re-sensitisation to cisplatin and resulted in re-expression of 41 of the down-regulated genes in cisplatin-resistant cells at the time point when re-sensitisation occurs. 13 of the 41 genes were consistently hypermethylated in two further independent cisplatin-resistant A2780 cell derivatives. Nine out of the 13 genes (ARHGDIB, ARMCX2, COL1A, FLNA, FLNC, MEST, MLH1, NTS, PSMB9) acquired methylation at CpG sites in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 candidate genes acquired methylation in drug-resistant in vivo-derived ovarian cancer sustaining (side population) cells. Therefore, this small set of genes are potential key drivers of chemoresistance and should be further evaluated as predictive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance. Array-based methylation profiling was performed using the Infinium HumanMethylation27 BeadChip in two cisplatin sensitive cell lines and three cisplatin resistant cell lines derived in vitro, four pairs of cisplatin sensitive and resistant cell lines derived in vivo, 7 pairs of tumour tissues obtained from patients before chemotherapy and at disease relapse, 2 pairs of IGROV1 SP and NSP cells. The reproducibility of the Infinium HumanMethylation27 BeadChips was evaluated using biological and technical replicates of matched chemosensitive/chemoresistant ovarian cancer cell lines PEO1/PEO4. Differential methylation cutoff was estimated from two biological replicates by bootstrap resampling.

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An epigenomic approach to identifying differential overlapping and cis-acting lncRNAs in cisplatin-resistant cancer cells

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