Abstract
Reduced levels of specific microRNA in cancer are frequently reported and associated with attenuated cancer genes and associated pathways. We previously reported a loss of miR-124a in glioblastoma (GBM) patient specimens; however, the upstream causes of this loss are largely unknown. Loss of miR-124a has been attributed to hypermethylation while other studies have shown miR-124a to be regulated by the repressor-element-1-silencing transcription factor (REST, also known as neuron-restrictive silencing factor). This current study looked at both epigenetic and transcription factor regulation as potential mechanisms resulting in the loss of miR-124a expression in GBM patient specimens and cell lines. Hypermethylation of miR-124a was observed in 82 % of GBM patient specimens (n = 56). In vitro miR-124a expression levels also increased after treatment of several patient-derived cell lines with 5-aza-2′-deoxycytidine. Additionally, we also demonstrated a positive interaction between REST activity and miR-124a using a luciferase-binding assay and we correlated the reciprocal expression of REST and miR-124a in our clinical cohort. This result indicates that miR-124a expression may also be modulated through the upstream targeting of REST. Preclinical studies involving inhibitors of REST and treatment with demethylating agents with the intent to increase miR-124a levels could be interesting.
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References
CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2004–2008. 2012.
Tivnan A, McDonald KL. Current progress for the use of miRNAs in glioblastoma treatment. Mol Neurobiol. 2013. doi:10.1007/s12035-013-8464-0
Novakova J, Slaby O, Vyzula R, Michalek J. MicroRNA involvement in glioblastoma pathogenesis. Biochem Biophys Res Commun. 2009;386:1–5.
Tong AW, Nemunaitis J. Modulation of miRNA activity in human cancer: a new paradigm for cancer gene therapy? Cancer Gene Ther. 2008;15:341–55.
Silber J, Hashizume R, Felix T, Hariono S, Yu M, Berger MS, et al. Expression of miR-124 inhibits growth of medulloblastoma cells. Neuro Oncol. 2013;15:83–90.
Xia H, Cheung WK, Ng SS, Jiang X, Jiang S, Sze J, et al. Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells. J Biol Chem. 2012;287:9962–71.
Conti L, Crisafulli L, Caldera V, Tortoreto M, Brilli E, Conforti P, et al. REST controls self-renewal and tumorigenic competence of human glioblastoma cells. PLoS One. 2012;7:e38486.
Skalsky RL, Cullen BR. Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene. PLoS One. 2011;6:e24248.
Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008;6:14.
Fowler A, Thomson D, Giles K, Maleki S, Mreich E, Wheeler H, et al. miR-124a is frequently down-regulated in glioblastoma and is involved in migration and invasion. Eur J Cancer. 2011;47:953–63.
Hua D, Mo F, Ding D, Li L, Han X, Zhao N, et al. A catalogue of glioblastoma and brain MicroRNAs identified by deep sequencing. OMICS: J Integr Biol. 2012;16:690–9.
Deng X, Ma L, Wu M, Zhang G, Jin C, Guo Y, et al. miR-124 radiosensitizes human glioma cells by targeting CDK4. J Neuro-Oncol. 2013;114(3):263–74.
Lang Q, Ling C. MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA. Biochem Biophys Res Commun. 2012;426:247–52.
Wei J, Wang F, Kong LY, Xu S, Doucette T, Ferguson SD, et al. miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res. 2013;73(13):3913–26.
Li D, Lu Z, Jia J, Zheng Z, Lin S. Changes in microRNAs associated with podocytic adhesion damage under mechanical stress. J Renin-Angiotensin-Aldosterone Syst JRAAS. 2013;14:97–102.
Lathia JD, Heddleston JM, Venere M, Rich JN. Deadly teamwork: neural cancer stem cells and the tumor microenvironment. Cell Stem Cell. 2011;8:482–5.
Furuta M, Kozaki KI, Tanaka S, Arii S, Imoto I, Inazawa J. miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma. Carcinogenesis. 2010;31:766–76.
Wong KY, So CC, Loong F, Chung LP, Lam WW, Liang R, et al. Epigenetic inactivation of the miR-124-1 in haematological malignancies. PLoS One. 2011;6:e19027.
Wilting SM, van Boerdonk RA, Henken FE, Meijer CJ, Diosdado B, Meijer GA, et al. Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer. Mol Cancer. 2010;9:167.
Wang X, Ren J, Wang Z, Yao J, Fei J. NRSF/REST is required for gastrulation and neurogenesis during zebrafish development. Acta Biochim Biophys Sin. 2012;44:385–93.
Gao Z, Ure K, Ding P, Nashaat M, Yuan L, Ma J, et al. The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells. J Neurosci Off J Soc Neurosci. 2011;31:9772–86.
Soldati C, Bithell A, Johnston C, Wong KY, Stanton LW, Buckley NJ. Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of Huntington's disease. J Neurochem. 2013;124:418–30.
Yu M, Suo H, Liu M, Cai L, Liu J, Huang Y, et al. NRSF/REST neuronal deficient mice are more vulnerable to the neurotoxin MPTP. Neurobiol Aging. 2013;34:916–27.
Liu M, Sheng Z, Cai L, Zhao K, Tian Y, Fei J. Neuronal conditional knockout of NRSF decreases vulnerability to seizures induced by pentylenetetrazol in mice. Acta Biochim Biophys Sin. 2012;44:476–82.
Yu M, Cai L, Liang M, Huang Y, Gao H, Lu S, et al. Alteration of NRSF expression exacerbating 1-methyl-4-phenyl-pyridinium ion-induced cell death of SH-SY5Y cells. Neurosci Res. 2009;65:236–44.
Taylor P, Fangusaro J, Rajaram V, Goldman S, Helenowski IB, MacDonald T, et al. REST is a novel prognostic factor and therapeutic target for medulloblastoma. Mol Cancer Ther. 2012;11:1713–23.
Fuller GN, Su X, Price RE, Cohen ZR, Lang FF, Sawaya R, et al. Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16. Mol Cancer Ther. 2005;4:343–9.
Su X, Gopalakrishnan V, Stearns D, Aldape K, Lang FF, Fuller G, et al. Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation. Mol Cell Biol. 2006;26:1666–78.
Kamal MM, Sathyan P, Singh SK, Zinn PO, Marisetty AL, Liang S, et al. REST regulates oncogenic properties of glioblastoma stem cells. Stem Cells. 2012;30:405–14.
Conaco C, Otto S, Han JJ, Mandel G. Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci U S A. 2006;103:2422–7.
Day BW, Stringer BW, Al-Ejeh F, Ting MJ, Wilson J, Ensbey KS, et al. EphA3 maintains tumorigenicity and is a therapeutic target in glioblastoma multiforme. Cancer Cell. 2013;23:238–48.
Lujambio A, Ropero S, Ballestar E, Fraga MF, Cerrato C, Setien F, et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 2007;67:1424–9.
Pierson J, Hostager B, Fan R, Vibhakar R. Regulation of cyclin dependent kinase 6 by microRNA 124 in medulloblastoma. J Neurooncol. 2008;90:1–7.
Fowler A, Cook R, Biggs M, Little N, Assaad N, McDonald K. Survival of patients following neurosurgical treatment of colorectal adenocarcinoma metastasis in the Northern Sydney-Central Coast area. J Clin Neurosci Off J Neurosurg Soc Australas. 2008;15:998–1004.
Das CM, Taylor P, Gireud M, Singh A, Lee D, Fuller G, et al. The deubiquitylase USP37 links REST to the control of p27 stability and cell proliferation. Oncogene. 2013;32:1691–701.
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Tivnan, A., Zhao, J., Johns, T.G. et al. The tumor suppressor microRNA, miR-124a, is regulated by epigenetic silencing and by the transcriptional factor, REST in glioblastoma. Tumor Biol. 35, 1459–1465 (2014). https://doi.org/10.1007/s13277-013-1200-6
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DOI: https://doi.org/10.1007/s13277-013-1200-6