Abstract
Cervical cancer (CC) is the fourth leading cause of cancer-associated mortalities among women worldwide. The chemotherapeutical platinum-based agent cisplatin (DDP) is the standard therapy for locally advanced or recurrent CC; however, platinum resistance limits its clinical benefit. Therefore, the present study aimed to identify key genes associated with DDP resistance in patients with CC and investigate the underlying molecular mechanisms. Firstly, using the CRISPR-Cas9 dataset of CC cells derived from DepMap portal, 699 genes associated with CC cell survival were identified. Subsequently, using the gene expression profiles of normal and CC samples with a response status to DDP, derived from The Cancer Genome Atlas (TCGA), hypoxia upregulated 1 (HYOU1) was further identified as significantly upregulated in CC samples and patients that did not respond to DDP (non-responders) when compared with healthy controls and patients that did respond to DDP (responders), respectively, using unpaired student's t-tests. Additionally, the log-rank test revealed that the high expression of HYOU1 was significantly associated with the poor survival of patients receiving DDP. The association between the high HYOU1 expression levels and the poor survival of patients receiving DDP was validated in the remaining TCGA dataset of patients with CC. HYOU1 expression levels were positively associated with the half-maximal inhibitory concentration value of DDP in CC cells using data derived from the Genomics of Drug Sensitivity in Cancer database. In vitro, western blotting experiments revealed high HYOU1 protein expression levels in DDP-resistant HeLa cells compared with their parental HeLa cells. Furthermore, the knockdown of HYOU1 resulted in an increased sensitivity of HeLa cells to DDP. Finally, using the sequence-based RNA adenosine methylation site predictor program, it was found that N6-methyladenosine (m6A) was highly enriched in HYOU1. The expression levels of the m6A reader, EIF3A, was positively correlated with the expression levels of HYOU1 and was upregulated in the non-response group compared with the response group in a dataset from TCGA database. Additionally, EIF3A had the highest probability of binding to the m6A motifs of HYOU1 compared with other genes. In GSE56363 obtained from the Gene Expression Omnibus, the non-responders had significantly increased expression levels of EIF3A compared with the responders. In conclusion, high expression levels of HYOU1, which may be regulated by EIF3A due to m6A modifications, was associated with DDP resistance in patients with CC and could potentially be used as an indicator of DDP treatment resistance.