Cisplatin-inducible death receptor 5 antisense long non-coding RNA modulates cell cycle and proliferation in HeLa cells

Abstract

Cisplatin is a chemotherapeutic drug with pleiotropic effects known to modulate the expression of long non-coding RNAs (lncRNAs). With the annotation of many novel lncRNAs, it is imperative to employ a more comprehensive approach to identify cisplatin-mediated changes in the expression of lncRNAs. Next generation sequencing (NGS)-based profiling of total RNAs from cisplatin-treated HeLa cells identified 3489 expressed lncRNAs, of which 1930 and 1051 were up- and downregulated upon cisplatin treatment, respectively. For functional analyses, we selected one of the cisplatin inducible lncRNAs situated antisense to the death receptor 5 and thus named death receptor 5 antisense lncRNA (DR5-AS). Knock-down of DR5-AS lncRNA caused a morphological change in cell shape without inducing any cell death. A second round of NGS-based profiling of total RNAs from DR5-AS-silenced cells revealed differential expression of genes associated with the immune system and cell cycle. Further analyses showed that DR5-AS reduces cell proliferation and causes a cell cycle arrest at S and G2/M phases. These results suggest that cisplatin-mediated reduction in cell proliferation and cell cycle may be mediated by long non-coding RNAs. SignificanceCisplatin is known to induce DNA-damage-induced cell death, which is used in combination chemotherapies in various cancer types. However, many patients develop resistance to cisplatin, which involves both protein-coding and noncoding genes. Although a number of long noncoding RNAs are linked to cisplatin resistance, a more comprehensive study is required. In this study, we took advantage of next-generation-sequencing based lncRNA profiling to unveil the extent of cisplatin inducible lncRNAs in HeLa cells. Additionally, we functionally characterized one of the cisplatin-inducible lncRNA, death receptor 5 antisense. Interestingly, this spesific lncRNA modulates cell morphology, proliferation and cell cycle without affecting cell death.