Abstract
IntroductionPatients with high‐grade glioma (HGG) suffered poor survival due to inherent or acquired therapeutic resistance and refractory recurrence. The outcome of HGG patients has improved little during the past decade. Therefore, molecular signatures are urgently needed for improving diagnosis, survival prediction and identification of therapeutic targets for HGG. E2F transcription factors (E2Fs), a family of transcription factors recognized as master regulators of cell proliferation, have been found to be involved in the pathogenesis of various tumor types.AimsTo investigate the expression of E2Fs and their prognosis value in high‐grade glioma (HGG).ResultsExpression of E2Fs was analyzed in 394 HGG samples from TCGA dataset. E2Fs were generally expressed in HGG. Except for E2F3 and E2F5, expression of E2Fs was significantly upregulated and linked with grade progression. E2F1, E2F2, E2F7, and E2F8 were highly correlated with aggressive proliferation oncogenes, as well as potential therapeutic resistance oncogenes. Elevated E2Fs (not E2F3) were associated with adverse tumor features and poorer outcome. E2F7 and E2F8 exhibited superior outcome prediction performance compared with other E2Fs. Additionally, E2F7 and E2F8 independently predicted poorer survival in HGG patients. Gene set enrichment analysis identified a variety of critical oncogenic pathways that were tightly associated with E2F7 or E2F8, including epithelial‐mesenchymal transition, NFκB, STAT3, angiogenesis pathways. Furthermore, elevated expression of E2F7 indicated worse therapeutic response of HGG to irradiation and silencing of E2F7 conferred higher cell‐killing effect when combined with irradiation treatment. Mechanically, E2F7 directly regulates the transcriptional activity of EZH2 via binding at the corresponding promoter area.ConclusionsE2Fs (except for E2F3 and E2F5) are highly expressed in HGG and indicate adverse outcome. E2F7 and E2F8 were identified as novel potential prognostic markers in HGG. E2F7 was further validated to be closely associated with radioresistance of HGG and a critical transcriptional regulator of EZH2.
Highlights
Patients with high-grade glioma (HGG) suffered poor survival due to inherent or acquired therapeutic resistance and refractory recurrence
Given the bigger median survival difference and higher area under the curve (AUC) value of E2F7 and E2F8, we further explore their link with clinical signature in HGG
High-grade glioma (HGG) demonstrates much worse outcome compared with the low-grade counterparts
Summary
Glioma is one of the most frequent and malignant primary brain tumors, accounting for more than 70% of adult brain tumors.[1]. In contrary to the previous defined function groups, some studies revealed that the atypical repressors played a critical role in conferring aggressiveness to tumor cells. Qing et al found that E2F8 transcriptionally promoted the expression of CCND1 via completely binding at the corresponding promoter area.[18] This raise a possibility that the function of E2Fs in tumor cells might be hijacked by oncogenic factor and confer to distinct or opposite function as we current know. Even though the E2Fs have been reported to tightly linked with malignant behavior of multiple cancer cells, the expression pattern and prognosis role of E2Fs have not been fully characterized in HGG. We investigated the expression profile of E2Fs, as well as the survival outcome in HGG patients via the analysis of TCGA dataset. The therapeutic resistance role of E2Fs was explored, and we further validated the critical role of E2F7 in promoting radioresistance
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