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.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507
Siegel RL, Miller KD, Jemal A (2017) Cancer Statistics, 2017. CA Cancer J Clin 67:7–30
Clarke J, Butowski N, Chang S (2010) Recent advances in therapy for glioblastoma. Arch Neurol 67:279–283
Jiang T, Mao Y, Ma W, Mao Q, You Y, Yang X, Jiang C, Kang C, Li X, Chen L, Qiu X, Wang W, Li W, Yao Y, Li S, Li S, Wu A, Sai K, Bai H, Li G, Chen B, Yao K, Wei X, Liu X, Zhang Z, Dai Y, Lv S, Wang L, Lin Z, Dong J, Xu G, Ma X, Cai J, Zhang W, Wang H, Chen L, Zhang C, Yang P, Yan W, Liu Z, Hu H, Chen J, Liu Y, Yang Y, Wang Z, Wang Z, Wang Y, You G, Han L, Bao Z, Liu Y, Wang Y, Fan X, Liu S, Liu X, Wang Y, Wang Q (2016) CGCG clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 375:263–273
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820
Chai RC, Zhang KN, Liu YQ, Wu F, Zhao Z, Wang KY, Jiang T (2019) Combinations of four or more CpGs methylation present equivalent predictive value for MGMT expression and temozolomide therapeutic prognosis in gliomas. CNS Neurosci Ther 25:314–322
Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. JAMA 310:1842–1850
Louis DN (2006) Molecular pathology of malignant gliomas. Annu Rev Pathol 1:97–117
Stupp R, Hegi ME, Gilbert MR, Chakravarti A (2007) Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol 25:4127–4136
Miller JJ, Wen PY (2016) Emerging targeted therapies for glioma. Expert opinion on emerging drugs 21:441–452
Shi X, Sun M, Liu H, Yao Y, Song Y (2013) Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett 339:159–166
Quinn JJ, Chang HY (2016) Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17:47–62
Gibb EA, Brown CJ, Lam WL (2011) The functional role of long non-coding RNA in human carcinomas. Mol Cancer 10:38
Porritt MJ, Batchelor PE, Howells DW (2005) Inhibiting BDNF expression by antisense oligonucleotide infusion causes loss of nigral dopaminergic neurons. Exp Neurol 192:226–234
Zheng X, Lin C, Li Y, Ye J, Zhou J, Guo P (2016) Long noncoding RNA BDNF-AS regulates ketamine-induced neurotoxicity in neural stem cell derived neurons. Biomed Pharmacother 82:722–728
Li Y, Xu F, Xiao H, Han F (2018) Long noncoding RNA BDNF-AS inversely regulated BDNF and modulated high-glucose induced apoptosis in human retinal pigment epithelial cells. J Cell Biochem 119:817–823
Zhao H, Diao C, Wang X, Xie Y, Liu Y, Gao X, Han J, Li S (2018) LncRNA BDNF-AS inhibits proliferation, migration, invasion and EMT in oesophageal cancer cells by targeting miR-214. J Cell Mol Med 22:3729–3739
Li W, Dou Z, We S, Zhu Z, Pan D, Jia Z, Liu H, Wang X, Yu G (2018) Long noncoding RNA BDNF-AS is associated with clinical outcomes and has functional role in human prostate cancer. Biomed Pharmacother 102:1105–1110
Zhang H, Liu C, Yan T, Wang J, Liang W (2018) Long noncoding RNA BDNF-AS is downregulated in cervical cancer and has anti-cancer functions by negatively associating with BDNF. Arch Biochem Biophys 646:113–119
Paz-Yaacov N, Bazak L, Buchumenski I, Porath HT, Danan-Gotthold M, Knisbacher BA, Eisenberg E, Levanon EY (2015) Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors. Cell Rep 13:267–276
Bass BL, Weintraub H (1988) An unwinding activity that covalently modifies its double-stranded RNA substrate. Cell 55:1089–1098
Galeano F, Tomaselli S, Locatelli F, Gallo A (2012) A-to-I RNA editing: the "ADAR" side of human cancer. Semin Cell Dev Biol 23:244–250
Slotkin W, Nishikura K (2013) Adenosine-to-inosine RNA editing and human disease. Genome Med 5:105
Chan TH, Qamra A, Tan KT, Guo J, Yang H, Qi L, Lin JS, Ng VH, Song Y, Hong H, Tay ST, Liu Y, Lee J, Rha SY, Zhu F, So JB, Teh BT, Yeoh KG, Rozen S, Tenen DG, Tan P, Chen L (2016) ADAR-mediated RNA editing predicts progression and prognosis of gastric cancer. Gastroenterology 151:637–650
Fritzell K, Xu LD, Lagergren J, Ohman M (2018) ADARs and editing: the role of A-to-I RNA modification in cancer progression. Semin Cell Dev Biol 79:123–130
Muller PA, Vousden KH (2014) Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25:304–317
Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, Barsyte-Lovejoy D, Al-awar R, Katona BW, Shilatifard A, Huang J, Hua X, Arrowsmith CH, Berger SL (2015) Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature 525:206–211
Leroy B, Fournier JL, Ishioka C, Monti P, Inga A, Fronza G, Soussi T (2013) The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis. Nucleic Acids Res 41:D962–D969
Liu S, Jiang T, Zhong Y, Yu Y (2019) miR-210 inhibits cell migration and invasion by targeting the brain-derived neurotrophic factor in glioblastoma. J Cell Biochem. https://doi.org/10.1002/jcb.28414
Chai Y, Liu J, Zhang Z, Liu L (2016) HuR-regulated lncRNA NEAT1 stability in tumorigenesis and progression of ovarian cancer. Cancer Med 5:1588–1598
Li Z, Wang Y, Hu R, Xu R, Xu W (2018) LncRNA B4GALT1-AS1 recruits HuR to promote osteosarcoma cells stemness and migration via enhancing YAP transcriptional activity. Cell Prolif 51:e12504
Zhou Y, Zhang X, Klibanski A (2012) MEG3 noncoding RNA: a tumor suppressor. J Mol Endocrinol 48:R45–R53
Shang W, Yang Y, Zhang J, Wu Q (2018) Long noncoding RNA BDNF-AS is a potential biomarker and regulates cancer development in human retinoblastoma. Biochem Biophys Res Commun 497:1142–1148
Wang Y, Zheng Y, Beal PA (2017) Adenosine deaminases that act on RNA (ADARs). Enzymes 41:215–268
Tomaselli S, Locatelli F, Gallo A (2014) The RNA editing enzymes ADARs: mechanism of action and human disease. Cell Tissue Res 356:527–532
Amin EM, Liu Y, Deng S, Tan KS, Chudgar N, Mayo MW, Sanchez-Vega F, Adusumilli PS, Schultz N, Jones DR (2017) The RNA-editing enzyme ADAR promotes lung adenocarcinoma migration and invasion by stabilizing FAK. Sci Signal. https://doi.org/10.1126/scisignal.aah3941
Zhang Y, Wang K, Zhao Z, Sun S, Zhang K, Huang R, Zeng F, Hu H (2018) ADAR3 expression is an independent prognostic factor in lower-grade diffuse gliomas and positively correlated with the editing level of GRIA2 (Q607R). Cancer Cell Int 18:196
Checler F, Alves da Costa C (2014) p53 in neurodegenerative diseases and brain cancers. Pharmacol Ther 142:99–113
Kitamura Y, Shimohama S, Kamoshima W, Matsuoka Y, Nomura Y, Taniguchi T (1997) Changes of p53 in the brains of patients with Alzheimer's disease. Biochem Biophys Res Commun 232:418–421
Al-Rugeebah A, Alanazi M, Parine NR (2019) MEG3: an oncogenic long non-coding RNA in different cancers. Pathol Oncol Res 25:859–874
Beckerman R, Prives C (2010) Transcriptional regulation by p53. Cold Spring Harb Perspect Biol 2:a000935
Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299
Preca BT, Bajdak K, Mock K, Lehmann W, Sundararajan V, Bronsert P, Matzge-Ogi A, Orian-Rousseau V, Brabletz S, Brabletz T, Maurer J, Stemmler MP (2017) A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer. Oncotarget 8:11530–11543
Ling Z, Wang X, Tao T, Zhang L, Guan H, You Z, Lu K, Zhang G, Chen S, Wu J, Qian J, Liu H, Xu B, Chen M (2017) Involvement of aberrantly activated HOTAIR/EZH2/miR-193a feedback loop in progression of prostate cancer. J Exp Clin Cancer Res 36:159
Chen Y, Bao C, Zhang X, Lin X, Huang H, Wang Z (2019) Long non-coding RNA HCG11 modulates glioma progression through cooperating with miR-496/CPEB3 axis. Cell Prolif 52:e12615
Zhang X, Du K, Lou Z, Ding K, Zhang F, Zhu J, Chang Z (2019) The CtBP1-HDAC1/2-IRF1 transcriptional complex represses the expression of the long noncoding RNA GAS5 in human osteosarcoma cells. Int J Biol Sci 15:1460–1471
The authors have a deep gratitude towards all lab members.
Conflict of interest
The authors declared that they have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
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
- Positive feedback loop