Abstract
BackgroundE2F transcription factors are considered to be important drivers of tumour growth. E2F7 is an atypical E2F factor, and its role in glioblastoma remains undefined.MethodsE2F7 expression was examined in patients by IHC and qRT-PCR. The overall survival probability was determined by statistical analyses. MTT assay, colony formation, cell-cycle assay, cell metastasis and the in vivo model were employed to determine the functional role of E2F7 in glioblastoma. Chromatin immunoprecipitation, luciferase assay and western blot were used to explore the underlying mechanisms.ResultsE2F7 was found to be up-regulated in glioblastoma patients, and high E2F7 expression was associated with poor overall survival in glioblastoma patients. Functional studies showed that E2F7 promoted cell proliferation, cell-cycle progression, cell metastasis and tumorigenicity abilities in vitro and in vivo. E2F7 promoted the transcription of EZH2 by binding to its promoter and increased H3K27me3 level. EZH2 recruited H3K27me3 to the promoter of PTEN and inhibited PTEN expression, and then activated the AKT/mTOR signalling pathway. In addition, restored expression of EZH2 recovered the abilities of cell proliferation and metastasis in E2F7-silencing cells.ConclusionCollectively, our findings indicate that E2F7 promotes cell proliferation, cell metastasis and tumorigenesis via EZH2-mediated PTEN/AKT/mTOR pathway in glioblastoma.
Highlights
E2F transcription factors are considered to be important drivers of tumour growth
All the results suggest that E2F7 serves as a promising marker for prognosis of glioblastoma patients
Restored expression of EZH2 in E2F7-silencing cells accelerated their proliferation and migration (Fig. 5f, g). These results suggested that E2F7−EZH2 axis triggers the AKT/mTOR pathway by inhibiting PTEN in glioblastoma
Summary
E2F transcription factors are considered to be important drivers of tumour growth. E2F7 is an atypical E2F factor, and its role in glioblastoma remains undefined. Glioblastoma (GBM) is the most common and aggressive subtype of primary malignant brain tumour in adults.[1,2] multimodality therapeutic scheme, including surgical resection and chemo radiation, has been accepted as a reliable therapy for the treatment of glioblastoma, the prognosis of glioblastoma patients is still very poor, with a median survival of about 15 months, which results in tumour recurrence.[3,4] The extreme ability of proliferation and invasion is due to anomalous genetic alterations and subsequent signal pathway stimulations.[5] the essential alterations involved in glioblastoma initiation and development remain elusive. E2F transcription factors are considered to be important drivers of tumour growth, which are involved in various progressions such as cell cycle, angiogenesis and DNAdamage response.[6,7,8,9] E2Fs are classified as typical E2Fs, including E2F1−E2F6 and atypical E2Fs (E2F7 and E2F8).[10] Typical E2Fs contain a conserved DBD domain (DNA binding) and a DIM domain (protein binding). Typical E2F proteins interact with DP protein to regulate transcription by binding to the promoter of target genes.[11,12] Unlike typical E2Fs, as an atypical E2F factor, E2F7 contains two individual DNA-binding domains, by which it binds to promoter sites of targets in a DPindependent manner.[13,14] E2F7 may function as a transcriptional repressor through competitive binding with E2F1 to consensus E2F-binding sites of target genes.[15,16,17] In addition, E2F7 has been shown to bind to CDH1 promoter in an E2F1-
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