Integrative analysis of a novel super-enhancer-associated lncRNA prognostic signature and identifying LINC00945 in aggravating glioma progression

Abstract

Background Super-enhancers (SEs), driving high-level expression of genes with tumor-promoting functions, have been investigated recently. However, the roles of super-enhancer-associated lncRNAs (SE-lncRNAs) in tumors remain undetermined, especially in gliomas. We here established a SE-lncRNAs expression-based prognostic signature to choose the effective treatment of glioma and identify a novel therapeutic target. Methods Combined analysis of RNA sequencing (RNA-seq) data and ChIP sequencing (ChIP-seq) data of glioma patient-derived glioma stem cells (GSCs) screened SE-lncRNAs. Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets served to construct and validate SE-lncRNA prognostic signature. The immune profiles and potential immuno- and chemotherapies response prediction value of the signature were also explored. Moreover, we verified the epigenetic activation mechanism of LINC00945 via the ChIP assay, and its effect on glioma was determined by performing the functional assay and a mouse xenograft model. Results 6 SE-lncRNAs were obtained and identified three subgroups of glioma patients with different prognostic and clinical features. A risk signature was further constructed and demonstrated to be an independent prognostic factor. The high-risk group exhibited an immunosuppressive microenvironment and was higher enrichment of M2 macrophage, regulatory T cells (Tregs), and Cancer-associated fibroblasts (CAFs). Patients in the high-risk group were better candidates for immunotherapy and chemotherapeutics. The SE of LINC00945 was further verified via ChIP assay. Mechanistically, BRD4 may mediate epigenetic activation of LINC00945. Additionally, overexpression of LINC00945 promoted glioma cell proliferation, EMT, migration, and invasion in vitro and xenograft tumor formation in vivo. Conclusion Our study constructed the first prognostic SE-lncRNA signature with the ability to optimize the choice of patients receiving immuno- and chemotherapies and provided a potential therapeutic target for glioma.

Super enhancer lncRNAs: a novel hallmark in cancer

“…Overexpression of LINC00945 promoted proliferation, EMT, migration, and invasion of glioma cells. Mechanistically, BRD4 mediated epigenetic activation of LINC00945 [ 44 ]. The study constructed the prognostic SE-lncRNA signature and provided a potential therapeutic target for glioma.…”

Research progress on function and mechanism of long non-coding RNA in glioma

“…Studies have revealed the significant regulatory role of lncRNA in gliomas, offering potential breakthroughs in the clinical diagnosis and treatment of gliomas [6,7]. At present, types, numbers and functions of lncRNA are not clear.…”