School of Biomedical Engineering, Capital Medical University, Beijing 100069, P.R. China.
Department of Anesthesiology, Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R. China.
Int J Mol Med. 2020 Jul;46(1):224-238. doi: 10.3892/ijmm.2020.4579. Epub 2020 Apr 15.
Glioblastoma (GBM) is a malignant brain tumor associated with high mortality. Long non‑coding RNAs (lncRNAs) are increasingly being recognized as its modulators. However, it remains mostly unexplored how lncRNAs are mediated by DNA methylation in GBM. The present study integrated multi‑omics data to analyze the epigenetic dysregulation of lncRNAs in GBM. Widely aberrant methylation in the lncRNA promoters was observed, and the lncRNA promoters exhibited a more hypomethylated pattern in GBM. By combining transcriptional datasets, it was possible identify the lncRNAs whose transcriptional changes might be associated with the aberrant promoter methylation. Then, a methylation‑mediated lncRNA regulatory network and functional enrichment analysis of aberrantly methylated lncRNAs showed that lncRNAs with different methylation patterns were involved in diverse GBM progression‑related biological functions and pathways. Specifically, four lncRNAs whose increased expression may be regulated by the corresponding promoter hypomethylation were evaluated to have an excellent diagnostic effect and clinical prognostic value. Finally, through the construction of drug‑target association networks, the present study identified potential therapeutic targets and small‑molecule drugs for GBM treatment. The present study provides novel insights for understanding the regulation of lncRNAs by DNA methylation and developing cancer biomarkers in GBM.
胶质母细胞瘤(GBM)是一种与高死亡率相关的恶性脑肿瘤。长链非编码 RNA(lncRNA)越来越被认为是其调节剂。然而,lncRNA 如何通过 DNA 甲基化在 GBM 中起作用在很大程度上仍未被探索。本研究整合了多组学数据来分析 GBM 中 lncRNA 的表观遗传失调。观察到 lncRNA 启动子广泛的异常甲基化,并且在 GBM 中 lncRNA 启动子表现出更去甲基化的模式。通过结合转录组数据集,有可能确定转录变化可能与异常启动子甲基化相关的 lncRNAs。然后,对甲基化介导的 lncRNA 调控网络和异常甲基化 lncRNA 的功能富集分析表明,具有不同甲基化模式的 lncRNAs 参与了不同的 GBM 进展相关的生物学功能和途径。具体来说,评估了四个表达增加可能受相应启动子低甲基化调节的 lncRNA,它们具有出色的诊断效果和临床预后价值。最后,通过构建药物-靶标关联网络,本研究确定了用于 GBM 治疗的潜在治疗靶点和小分子药物。本研究为理解 DNA 甲基化对 lncRNA 的调控以及开发 GBM 中的癌症生物标志物提供了新的见解。