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Cellular and Molecular Biology

E2F7−EZH2 axis regulates PTEN/AKT/mTOR signalling and glioblastoma progression

Abstract

Background

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.

Methods

E2F7 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.

Results

E2F7 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.

Conclusion

Collectively, our findings indicate that E2F7 promotes cell proliferation, cell metastasis and tumorigenesis via EZH2-mediated PTEN/AKT/mTOR pathway in glioblastoma.

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Fig. 1: E2F7 expression is increased and correlated with poor outcomes.
Fig. 2: E2F7 is important for cell proliferation in glioblastoma.
Fig. 3: E2F7 promotes cell migration and invasion in glioblastoma.
Fig. 4: E2F7 is a direct transcriptional activator of EZH2 expression.
Fig. 5: E2F7−EZH2 axis triggers the AKT/mTOR pathway.
Fig. 6: E2F7 promotes tumorigenesis by regulating PTEN/AKT/mTOR pathway in glioblastoma.

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Acknowledgements

We thank all the participants for their contributions to the study.

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Affiliations

Authors

Contributions

Conception and design: R.Y., H.C. Acquisition of data: R.Y., M.W., G.Z., Y.W., X.L. Analysis and interpretation: R.Y., Y.B., W.Y., H.C. Original manuscript drafting and figure construction: R.Y. Manuscript editing and completion: R.Y., M.W., H.C.

Corresponding authors

Correspondence to Rui Yang or Hongjuan Cui.

Ethics declarations

Ethics approval and consent to participate

The trial protocol was compliant with good clinical practice guidelines and the Declaration of Helsinki and was approved by the ethics committee of The Second People’s Hospital of Liaocheng. All patients provided written informed consent before participation. Animal experiments were performed in compliance with the guidelines of the Institute for Laboratory Animal Research, Jining Medical University, China.

Data availability

Data and material shall be available from the corresponding authors.

Competing interests

The authors declare no competing interests.

Funding information

This research was supported by the National Natural Science Foundation of China (Grants 81672502 and 81602479), the National Natural Science Foundation Cultivation Project of Jining Medical University (JYP2019KJ02) and faculty Start-up Fund for R.Y. from Jining Medical University (600788001).

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Yang, R., Wang, M., Zhang, G. et al. E2F7−EZH2 axis regulates PTEN/AKT/mTOR signalling and glioblastoma progression. Br J Cancer 123, 1445–1455 (2020). https://doi.org/10.1038/s41416-020-01032-y

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