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Current Pharmaceutical Biotechnology

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ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

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Research Article

DBX2 Promotes Glioblastoma Cell Proliferation by Regulating REST Expression

Author(s): Ruixing He, Xiaotian Zhang and Lianshu Ding*

Volume 23, Issue 8, 2022

Published on: 30 August, 2021

Page: [1101 - 1108] Pages: 8

DOI: 10.2174/1389201022666210830142827

Price: $65

Abstract

Background: Glioblastoma (GBM) is the most common but lethal brain cancer with poor prognosis. The developing brain homeobox 2 (DBX2) has been reported to play important roles in tumor growth. However, the mechanisms of DBX2 in GBM are still unknown.

Objectives: This study aims to investigate the function and mechanisms of DBX2 in GBM.

Methods: The expressions of DBX2 and REST in GBM were measured by analyzing data from databases, and the results were checked by qPCR and/or western blot of GBM cell lines. Cell proliferation was determined by CCK8 assay, immunohistochemistry and colony formation assay. ChIP-qPCR was used to determine the binding sites of DBX2 on REST.

Results: In this study, we found that the expression of DBX2 was upregulated in the GBM cell lines. The cell proliferation was damaged after blocking DBX2 expression in U87 and U251 GBM cell lines. The expression level of DBX2 had a positive relationship with that of REST. Our ChIPqPCR results showed that DBX2 is directly bound to the promoter region of REST. Additionally, the increased GBM cell proliferation caused by DBX2 overexpression can be rescued by REST loss of function.

Conclusion: DBX2 could promote cell proliferation of GBM by binding to the promoter region of REST gene and increasing REST expression.

Keywords: DBX2, Glioblastoma, REST, tumor growth, cell proliferation, GBM.

« Previous Next »
[1]
Wirsching, H.G.; Galanis, E.; Weller, M. Glioblastoma. Handb. Clin. Neurol., 2016, 134, 381-397.
[http://dx.doi.org/10.1016/B978-0-12-802997-8.00023-2] [PMID: 26948367]
[2]
Duffau, H. Glioblastoma in 2017. Rev. Infirm., 2017, 66(228), 16-18. [Glioblastoma in 2017]
[http://dx.doi.org/10.1016/j.revinf.2016.12.002] [PMID: 28160825]
[3]
Le Rhun, E.; Preusser, M.; Roth, P.; Reardon, D.A.; van den Bent, M.; Wen, P.; Reifenberger, G.; Weller, M. Molecular targeted therapy of glioblastoma. Cancer Treat. Rev., 2019, 80, 101896.
[http://dx.doi.org/10.1016/j.ctrv.2019.101896] [PMID: 31541850]
[4]
Eder, K.; Kalman, B. Molecular heterogeneity of glioblastoma and its clinical relevance. Pathol. Oncol. Res., 2014, 20(4), 777-787.
[http://dx.doi.org/10.1007/s12253-014-9833-3] [PMID: 25156108]
[5]
Campos, B.; Olsen, L.R.; Urup, T.; Poulsen, H.S. A comprehensive profile of recurrent glioblastoma. Oncogene, 2016, 35(45), 5819-5825.
[http://dx.doi.org/10.1038/onc.2016.85] [PMID: 27041580]
[6]
Marisetty, A.L.; Lu, L.; Veo, B.L.; Liu, B.; Coarfa, C.; Kamal, M.M.; Kassem, D.H.; Irshad, K.; Lu, Y.; Gumin, J.; Henry, V.; Paulucci-Holthauzen, A.; Rao, G.; Baladandayuthapani, V.; Lang, F.F.; Fuller, G.N.; Majumder, S. REST-DRD2 mechanism impacts glioblastoma stem cell-mediated tumorigenesis. Neuro-oncol., 2019, 21(6), 775-785.
[http://dx.doi.org/10.1093/neuonc/noz030] [PMID: 30953587]
[7]
Zhang, D.; Li, Y.; Wang, R.; Li, Y.; Shi, P.; Kan, Z.; Pang, X. Inhibition of REST Suppresses Proliferation and Migration in Glioblastoma Cells. Int. J. Mol. Sci., 2016, 17(5), E664.
[http://dx.doi.org/10.3390/ijms17050664] [PMID: 27153061]
[8]
Liu, T.; Xu, H.; Huang, M.; Ma, W.; Saxena, D.; Lustig, R.A.; Alonso-Basanta, M.; Zhang, Z.; O’Rourke, D.M.; Zhang, L.; Gong, Y.; Kao, G.D.; Dorsey, J.F.; Fan, Y. Circulating Glioma Cells Exhibit Stem Cell-like Properties. Cancer Res., 2018, 78(23), 6632-6642.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-0650] [PMID: 30322863]
[9]
Kamal, M.M.; Sathyan, P.; Singh, S.K.; Zinn, P.O.; Marisetty, A.L.; Liang, S.; Gumin, J.; El-Mesallamy, H.O.; Suki, D.; Colman, H.; Fuller, G.N.; Lang, F.F.; Majumder, S. REST regulates oncogenic properties of glioblastoma stem cells. Stem Cells, 2012, 30(3), 405-414.
[http://dx.doi.org/10.1002/stem.1020] [PMID: 22228704]
[10]
Lu, S.; Bogarad, L.D.; Murtha, M.T.; Ruddle, F.H. Expression pattern of a murine homeobox gene, Dbx, displays extreme spatial restriction in embryonic forebrain and spinal cord. Proc. Natl. Acad. Sci. USA, 1992, 89(17), 8053-8057.
[http://dx.doi.org/10.1073/pnas.89.17.8053] [PMID: 1355604]
[11]
Gribble, S.L.; Nikolaus, O.B.; Dorsky, R.I. Regulation and function of Dbx genes in the zebrafish spinal cord. Dev. Dyn., 2007, 236(12), 3472-3483.
[http://dx.doi.org/10.1002/dvdy.21367] [PMID: 17994542]
[12]
Ma, P.; Zhao, S.; Zeng, W.; Yang, Q.; Li, C.; Lv, X.; Zhou, Q.; Mao, B. Xenopus Dbx2 is involved in primary neurogenesis and early neural plate patterning. Biochem. Biophys. Res. Commun., 2011, 412(1), 170-174.
[http://dx.doi.org/10.1016/j.bbrc.2011.07.068] [PMID: 21806971]
[13]
Pierani, A.; Brenner-Morton, S.; Chiang, C.; Jessell, T.M. A sonic hedgehog-independent, retinoid-activated pathway of neurogenesis in the ventral spinal cord. Cell, 1999, 97(7), 903-915.
[http://dx.doi.org/10.1016/S0092-8674(00)80802-8] [PMID: 10399918]
[14]
Lupo, G.; Nisi, P.S.; Esteve, P.; Paul, Y.L.; Novo, C.L.; Sidders, B.; Khan, M.A.; Biagioni, S.; Liu, H.K.; Bovolenta, P.; Cacci, E.; Rugg-Gunn, P.J. Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age-associated neurogenic decline. Aging Cell, 2018, 17(3), e12745.
[http://dx.doi.org/10.1111/acel.12745] [PMID: 29504228]
[15]
Hu, Y.T.; Li, B.F.; Zhang, P.J.; Wu, D.; Li, Y.Y.; Li, Z.W.; Shen, L.; Dong, B.; Gao, J.; Zhu, X. Dbx2 exhibits a tumor-promoting function in hepatocellular carcinoma cell lines via regulating Shh-Gli1 signaling. World J. Gastroenterol., 2019, 25(8), 923-940.
[http://dx.doi.org/10.3748/wjg.v25.i8.923] [PMID: 30833799]
[16]
Ooi, L.; Wood, I.C. Chromatin crosstalk in development and disease: Lessons from REST. Nat. Rev. Genet., 2007, 8(7), 544-554.
[http://dx.doi.org/10.1038/nrg2100] [PMID: 17572692]
[17]
Chong, J.A.; Tapia-Ramírez, J.; Kim, S.; Toledo-Aral, J.J.; Zheng, Y.; Boutros, M.C.; Altshuller, Y.M.; Frohman, M.A.; Kraner, S.D.; Mandel, G. REST: A mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell, 1995, 80(6), 949-957.
[http://dx.doi.org/10.1016/0092-8674(95)90298-8] [PMID: 7697725]
[18]
Ballas, N.; Grunseich, C.; Lu, D.D.; Speh, J.C.; Mandel, G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell, 2005, 121(4), 645-657.
[http://dx.doi.org/10.1016/j.cell.2005.03.013] [PMID: 15907476]
[19]
Bruce, A.W.; López-Contreras, A.J.; Flicek, P.; Down, T.A.; Dhami, P.; Dillon, S.C.; Koch, C.M.; Langford, C.F.; Dunham, I.; Andrews, R.M.; Vetrie, D. Functional diversity for REST (NRSF) is defined by in vivo binding affinity hierarchies at the DNA sequence level. Genome Res., 2009, 19(6), 994-1005.
[http://dx.doi.org/10.1101/gr.089086.108] [PMID: 19401398]
[20]
Huang, Z.; Bao, S. Ubiquitination and deubiquitination of REST and its roles in cancers. FEBS Lett., 2012, 586(11), 1602-1605.
[http://dx.doi.org/10.1016/j.febslet.2012.04.052] [PMID: 22569092]
[21]
Zhao, Y.; Zhu, M.; Yu, Y.; Qiu, L.; Zhang, Y.; He, L.; Zhang, J. Brain REST/NRSF Is Not Only a Silent Repressor but Also an Active Protector. Mol. Neurobiol., 2017, 54(1), 541-550.
[http://dx.doi.org/10.1007/s12035-015-9658-4] [PMID: 26742529]
[22]
Roveda, E.; Bruno, E.; Galasso, L.; Mulè, A.; Castelli, L.; Villarini, A.; Caumo, A.; Esposito, F.; Montaruli, A.; Pasanisi, P. Rest-activity circadian rhythm in breast cancer survivors at 5 years after the primary diagnosis. Chronobiol. Int., 2019, 36(8), 1156-1165.
[http://dx.doi.org/10.1080/07420528.2019.1621330] [PMID: 31177874]
[23]
Conti, L.; Crisafulli, L.; Caldera, V.; Tortoreto, M.; Brilli, E.; Conforti, P.; Zunino, F.; Magrassi, L.; Schiffer, D.; Cattaneo, E. REST controls self-renewal and tumorigenic competence of human glioblastoma cells. PLoS One, 2012, 7(6), e38486.
[http://dx.doi.org/10.1371/journal.pone.0038486] [PMID: 22701651]
[24]
Lee, E.; Yong, R.L.; Paddison, P.; Zhu, J. Comparison of glioblastoma (GBM) molecular classification methods. Semin. Cancer Biol., 2018, 53, 201-211.
[http://dx.doi.org/10.1016/j.semcancer.2018.07.006] [PMID: 30031763]
[25]
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 2008, 455(7216), 1061-1068.
[http://dx.doi.org/10.1038/nature07385] [PMID: 18772890]
[26]
Kim, Y.; Yoon, J.W.; Xiao, X.; Dean, N.M.; Monia, B.P.; Marcusson, E.G. Selective down-regulation of glioma-associated oncogene 2 inhibits the proliferation of hepatocellular carcinoma cells. Cancer Res., 2007, 67(8), 3583-3593.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-3040] [PMID: 17440069]
[27]
Singh, S.K.; Kagalwala, M.N.; Parker-Thornburg, J.; Adams, H.; Majumder, S. REST maintains self-renewal and pluripotency of embryonic stem cells. Nature, 2008, 453(7192), 223-227.
[http://dx.doi.org/10.1038/nature06863] [PMID: 18362916]
[28]
Gopalakrishnan, V. REST and the RESTless: In stem cells and beyond. Future Neurol., 2009, 4(3), 317-329.
[http://dx.doi.org/10.2217/fnl.09.1] [PMID: 19885378]
[29]
Westbrook, T.F.; Martin, E.S.; Schlabach, M.R.; Leng, Y.; Liang, A.C.; Feng, B.; Zhao, J.J.; Roberts, T.M.; Mandel, G.; Hannon, G.J.; Depinho, R.A.; Chin, L.; Elledge, S.J. A genetic screen for candidate tumor suppressors identifies REST. Cell, 2005, 121(6), 837-848.
[http://dx.doi.org/10.1016/j.cell.2005.03.033] [PMID: 15960972]
[30]
Wagoner, M.P.; Gunsalus, K.T.; Schoenike, B.; Richardson, A.L.; Friedl, A.; Roopra, A. The transcription factor REST is lost in aggressive breast cancer. PLoS Genet., 2010, 6(6), e1000979.
[http://dx.doi.org/10.1371/journal.pgen.1000979] [PMID: 20548947]
[31]
Coulson, J.M.; Edgson, J.L.; Woll, P.J.; Quinn, J.P. A splice variant of the neuron-restrictive silencer factor repressor is expressed in small cell lung cancer: A potential role in derepression of neuroendocrine genes and a useful clinical marker. Cancer Res., 2000, 60(7), 1840-1844.
[PMID: 10766169]
[32]
Lawinger, P.; Venugopal, R.; Guo, Z.S.; Immaneni, A.; Sengupta, D.; Lu, W.; Rastelli, L.; Marin Dias Carneiro, A.; Levin, V.; Fuller, G.N.; Echelard, Y.; Majumder, S. The neuronal repressor REST/NRSF is an essential regulator in medulloblastoma cells. Nat. Med., 2000, 6(7), 826-831.
[http://dx.doi.org/10.1038/77565] [PMID: 10888935]

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