Dissecting drug and prognostic lncRNA signature mediated by DNA methylation and transcription factor in colon cancer

Abstract

Background: Colon cancer is still the most commonly diagnosed malignancy and leading cause of death worldwide. Apart from living habits, genetic and epigenetic changes are key factors to influence the risk of colon cancer. However, the impact of epigenetic alterations in non-coding RNAs and the consequences for colon cancer has not been fully characterized.Methods: We detected differential methylation sites (DMSs) in lncRNA promoters, and identified lncQTMs by association test. To investigate TF binding affected by DNA methylation, we characterized known TF motif occurrence among DMSs collected from MEME suit. We further combined methylome and transcriptome data to construct TF-methylation-lncRNA relationships. To study the role of lncRNAs in drug response, we used pharmacological and lncRNA profiles derived from CCLE and predict drug response by lncRNA expression level. We also used the combination of TF-methylation-lncRNA relationship to stratified patient survival information by a risk model.Results: DNA methylation display global hyper-methylation character in lncRNA promoters, and they tend to have negative relationship with the corresponding lncRNAs. Negative lncQTMs located near TSS have more significant and stronger correlation with the corresponding lncRNAs. Some lncRNAs mediated by the interplay between DNA methylation and TFs are proved markers for colon cancer. Typically, lncRNA CAHM, RP11-834C11.4 and LINC00460 are good predictors for 5 drug components (17-AAG, Sorafenib, TKI258, RAF265, Topotecan) in colon cancer. And we found HES1_cg24685006_RP4-728D4.2 and SREBF1_cg05372727_LINC00460 relationships are prognostic signatures for colon cancer.Conclusions: These findings suggested lncRNAs mediated by the interplay between DNA methylation and TFs are promising predictors for drug response, besides, combined TF-methylation-lncRNA can serve as prognostic signature for colon cancer.