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Activation of BDNF-AS/ADAR/p53 Positive Feedback Loop Inhibits Glioblastoma Cell Proliferation

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Abstract

Despite progress in conventional treatment for glioblastoma (GBM), the prognosis remains poor due to high tumor recurrence. Therefore, identification of new molecular mechanisms is a pressing need for betterment of GBM patient outcomes. qRT-PCR was used to determine BDNF-AS expression in GBM cells. CCK-8, EdU incorporation, and caspase-3 activity assays were employed to analyze biological functions of BDNF-AS. RIP and RNA pull-down were conducted to detect the interactions among BDNF-AS, ADAR, and p53. Actinomycin D was utilized to examine the stability of p53 mRNA. ChIP and luciferase reporter assays were performed to detect transcriptional activation of BDNF-AS by p53. We found that BDNF-AS was significantly downregulated in GBM cell lines, and its overexpression inhibited GBM cell growth, and promoted apoptosis. Importantly, we illustrated that BDNF-AS coupled with ADAR protein to potentiate stability of p53 mRNA and thus upregulate p53. Interestingly, we further identified p53 as a transcription factor of BDNF-AS, activating transcription of BNDF-AS. This study firstly demonstrated that BDNF-AS acted as a tumor suppressor in GBM and the positive feedback circuit of BDNF-AS/ADAR/p53 served an important mechanism to control GBM proliferation. Targeting this auto-regulatory loop may provide a potential therapeutic strategy for GBM patients.

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Acknowledgements

The authors have a deep gratitude towards all lab members.

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Correspondence to Shiwen Guo.

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Lv, X., Gu, C. & Guo, S. Activation of BDNF-AS/ADAR/p53 Positive Feedback Loop Inhibits Glioblastoma Cell Proliferation. Neurochem Res 45, 508–518 (2020). https://doi.org/10.1007/s11064-019-02943-w

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Keywords

  • Glioblastoma
  • BDNF-AS
  • ADAR
  • p53
  • Positive feedback loop