title: Critical role of zinc finger protein 521 in the control of growth, clonogenicity and tumorigenic potential of medulloblastoma cells.
abstract: The stem cell-associated transcription co-factor ZNF521 has been implicated in the control of hematopoietic, osteo-adipogenic and neural progenitor cells. ZNF521 is highly expressed in cerebellum and in particular in the neonatal external granule layer that contains candidate medulloblastoma cells-of-origin, and in the majority of human medulloblastomas. Here we have explored its involvement in the control of human and murine medulloblastoma cells. The effect of ZNF521 on growth and tumorigenic potential of human medulloblastoma cell lines as well as primary Ptc1-/+ mouse medulloblastoma cells was investigated in a variety of in vitro and in vivo assays, by modulating its expression using lentiviral vectors carrying the ZNF521 cDNA, or shRNAs that silence its expression. Enforced overexpression of ZNF521 in DAOY medulloblastoma cells significantly increased their proliferation, growth as spheroids and ability to generate clones in single-cell cultures and semisolid media, and enhanced their migratory ability in wound-healing assays. Importantly, ZNF521-expressing cells displayed a greatly enhanced tumorigenic potential in nude mice. All these activities required the ZNF521 N-terminal motif that recruits the nucleosome remodeling and histone deacetylase complex, which might therefore represent an appealing therapeutic target. Conversely, silencing of ZNF521 in human UW228 medulloblastoma cells that display high baseline expression decreased their proliferation, clonogenicity, sphere formation and wound-healing ability. Similarly, Zfp521 silencing in mouse Ptc1-/+ medulloblastoma cells drastically reduced their growth and tumorigenic potential. Our data strongly support the notion that ZNF521, through the recruitment of the NuRD complex, contributes to the clonogenic growth, migration and tumorigenicity of medulloblastoma cells.
authors.affiliation: Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University of Catanzaro Magna Græcia, Catanzaro, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Spina
authors.forename: Gessica
authors.initials: G
authors.lastname: Filocamo
authors.forename: Enrico
authors.initials: E
authors.lastname: Iaccino
authors.forename: Stefania
authors.initials: S
authors.lastname: Scicchitano
authors.forename: Michela
authors.initials: M
authors.lastname: Lupia
authors.forename: Emanuela
authors.initials: E
authors.lastname: Chiarella
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mega
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernaudo
authors.forename: Daniela
authors.initials: D
authors.lastname: Pelaggi
authors.forename: Maria
authors.initials: M
authors.lastname: Mesuraca
authors.forename: Simonetta
authors.initials: S
authors.lastname: Pazzaglia
authors.forename: Samantha
authors.initials: S
authors.lastname: Semenkow
authors.forename: Eli E
authors.initials: EE
authors.lastname: Bar
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Heather M
authors.initials: HM
authors.lastname: Bond
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.forename: Giovanni
authors.initials: G
authors.lastname: Morrone
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D020014:K562 Cells; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; C529598:zinc finger protein 521, human
references.citation: Nat Neurosci. 2006 Mar;9(3):443-52
references.pmid: 16491081
references.citation: Mol Cell Biol. 2010 Aug;30(16):4045-59
references.pmid: 20547755
references.citation: Bone. 2009 Apr;44(4):528-36
references.pmid: 19095088
references.citation: Dev Cell. 2010 Oct 19;19(4):533-46
references.pmid: 20951345
references.citation: Nature. 2002 Jan 24;415(6870):436-42
references.pmid: 11807556
references.citation: Nature. 2012 Aug 2;488(7409):43-8
references.pmid: 22722829
references.citation: PLoS One. 2011 Jan 05;6(1):e15844
references.pmid: 21246056
references.citation: Neurogenetics. 2006 May;7(2):67-80
references.pmid: 16572319
references.citation: J Clin Oncol. 2011 Apr 10;29(11):1424-30
references.pmid: 21098324
references.citation: J Biol Chem. 2007 Nov 30;282(48):34858-68
references.pmid: 17895244
references.citation: Cell Cycle. 2010 Jun 1;9(11):2047-8
references.pmid: 20505339
references.citation: J Cell Biol. 2010 Dec 27;191(7):1271-83
references.pmid: 21173110
references.citation: Oncotarget. 2011 Dec;2(12):976-83
references.pmid: 22249030
references.citation: J Exp Med. 2013 May 6;210(5):969-85
references.pmid: 23569325
references.citation: Nature. 2011 Feb 24;470(7335):503-9
references.pmid: 21326203
references.citation: Dev Biol. 2007 Jul 1;307(1):43-52
references.pmid: 17524391
references.citation: Science. 1997 Aug 22;277(5329):1109-13
references.pmid: 9262482
references.citation: Blood. 2010 Mar 18;115(11):2156-66
references.pmid: 20065294
references.citation: Trends Neurosci. 2011 Mar;34(3):134-42
references.pmid: 21315459
references.citation: Cancer Res. 2000 Apr 15;60(8):2239-46
references.pmid: 10786690
references.citation: J Clin Oncol. 2011 Apr 10;29(11):1408-14
references.pmid: 20823417
references.citation: J Immunol. 2009 Apr 15;182(8):4529-37
references.pmid: 19342626
references.citation: Cell Cycle. 2011 Jul 1;10(13):2129-39
references.pmid: 21593590
references.citation: Oncotarget. 2011 Aug;2(8):590-8
references.pmid: 21896959
references.citation: Int J Biochem Cell Biol. 2008;40(5):848-54
references.pmid: 17543573
references.citation: Nat Methods. 2006 Oct;3(10):801-6
references.pmid: 16990812
references.citation: Stem Cells. 2007 Apr;25(4):871-4
references.pmid: 17185607
references.citation: J Pathol. 2009 May;218(1):86-94
references.pmid: 19197950
references.citation: Cell Cycle. 2012 May 1;11(9):1841-50
references.pmid: 22544282
references.citation: EMBO J. 2005 Jul 6;24(13):2367-78
references.pmid: 15920470
references.citation: PLoS Biol. 2012;10(11):e1001433
references.pmid: 23209378
references.citation: PLoS One. 2009;4(5):e5577
references.pmid: 19440552
references.citation: J Clin Oncol. 2006 Apr 20;24(12):1924-31
references.pmid: 16567768
references.citation: EMBO J. 2010 Jan 20;29(2):442-56
references.pmid: 19927129
references.citation: J Biol Chem. 2004 Dec 31;279(53):55017-23
references.pmid: 15507435
references.citation: Cell Mol Life Sci. 2013 Oct;70(19):3513-24
references.pmid: 23340908
references.citation: PLoS One. 2008 Aug 28;3(8):e3088
references.pmid: 18769486
references.citation: Nat Rev Cancer. 2010 May;10(5):319-31
references.pmid: 20414201
references.citation: Cancer Res. 2006 Apr 15;66(8):4215-22
references.pmid: 16618744
references.citation: Acta Neuropathol. 2012 Apr;123(4):465-72
references.pmid: 22134537
references.citation: Nat Cell Biol. 2010 Feb;12(2):132-42
references.pmid: 20081843
references.citation: Blood. 2004 Mar 15;103(6):2062-70
references.pmid: 14630787
references.citation: Oncogene. 2010 Apr 1;29(13):1963-75
references.pmid: 20062079
references.citation: Blood. 2003 Mar 1;101(5):1934-40
references.pmid: 12393497
references.citation: Trends Mol Med. 2005 Jan;11(1):17-22
references.pmid: 15649818
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19424-9
references.pmid: 17151198
references.citation: Mol Cell Biol. 2006 Sep;26(18):6913-22
references.pmid: 16943432
references.citation: Nat Rev Cancer. 2011 Jul 07;11(8):588-96
references.pmid: 21734722
references.citation: Oncotarget. 2011 Dec;2(12):984-96
references.pmid: 22184287
references.citation: J Neuropathol Exp Neurol. 1985 Sep;44(5):472-85
references.pmid: 2993532
references.citation: Stem Cells. 2009 Nov;27(11):2815-23
references.pmid: 19785032
references.citation: Cell Cycle. 2012 Sep 15;11(18):3358-69
references.pmid: 22894929
references.citation: Oncogene. 2002 Oct 24;21(49):7580-4
references.pmid: 12386820
references.citation: Nature. 2010 Dec 23;468(7327):1095-9
references.pmid: 21150899
references.citation: J Biol Chem. 2009 Feb 6;284(6):3480-7
references.pmid: 19049973
references.citation: Cancer Cell. 2012 Feb 14;21(2):137-8
references.pmid: 22340583