Aberrant Methylation Modifications Reflect Specific Drug Responses in Small Cell Lung Cancer

Abstract

Background: Epigenetic alterations of specific genes are closely related to chemotherapeutic efficacy in various cancers. However, few comprehensive profiles of differentially methylated genes (DMGs) in small cell lung cancer (SCLC) were available. The current study aimed to explore the association between aberrant methylation modifications of coding and non-coding genes and chemotherapy insensitivity, thus constructing lncRNA-miRNA-mRNA regulatory network in SCLC.Methods: In this study, methylated DNA immunoprecipitation sequencing (MeDIP-Seq) and RNA sequencing (RNA-Seq) was employed to six SCLC patients who were sensitive and insensitive to first-line standard chemotherapy. Then, we verified the therapeutic predictive effects of DMGs in 62 SCLC cell lines and constructed lncRNA-miRNA-mRNA network on the basis of different cohorts and databases. Results: Of 4552 DMGs which were selected (fold change ≥ 2, p<0.01) between chemo-sensitive and chemo-insensitive group, coding genes constituted the largest percentage (3873/4551, 85.08%), followed by lncRNAs (479/4551, 10.52%) and miRNAs (162/4552, 3.56%). Further, both two groups demonstrated two methylation peaks near transcription start site and transcription end site. Two lncRNA-miRNA-mRNA networks which based on genes that showed opposite results in genetic expression and epigenetic modifications suggested the extensive genome connection between chemotherapy efficacy-related non-coding RNAs (ncRNAs) and mRNAs. Combing four DMGs, including hsa-miR-34a, LINC00461, LINC01018, and LINC01484 could effectively predict first-line chemotherapy response in SCLC, indicating that they might play vital roles in SCLC chemotherapy insensitivity. Conclusions: This study was the first to evaluate multiple drugs efficacy-related ncRNAs and mRNAs which were modified by methylation in SCLC. In addition, DMGs identified in our research might serve as predictors for chemotherapy effect and promising therapeutic targets to reverse drugs-insensitivity by complex lncRNA-miRNA-mRNA mechanisms in SCLC. Further comprehensive studies of these findings are worthy of expecting.