Critical role of zinc finger protein 521 in the control of growth, clonogenicity and tumorigenic potential of medulloblastoma cells.
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Raffaella Spina1,3,7,*, Gessica Filocamo2,*, Enrico Iaccino1, Stefania Scicchitano1, Michela Lupia1, Emanuela Chiarella1, Tiziana Mega1, Francesca Bernaudo1, Daniela Pelaggi1, Maria Mesuraca1, Simonetta Pazzaglia4, Samantha Semenkow3, Eli E. Bar3,7, Marcel Kool5, Stefan Pfister5,6, Heather M. Bond1, Charles G. Eberhart3, Christian Steinkühler2, Giovanni Morrone1
1 Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University of Catanzaro Magna Græcia, Catanzaro, Italy.
2 Exiris srl, Via Castelfidardo 8, Rome, Italy.
3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore MD, USA.
4 Section of Toxicology and Biomedical Sciences, ENEA CR-Casaccia, Via Anguillarese 301, S.Maria di Galeria (Roma), Italy.
5 Division of Pediatric Neurooncology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, Germany.
6 Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany
7 Current address: Department of Neurological Surgery, Case Western Reserve University, Cleveland, Ohio, USA.
* These authors contributed equally to this work
Giovanni Morrone, email:
Christian Steinkühler, email:
Charles G. Eberhart, email:
Keywords: ZNF521; gene expression; medulloblastoma; cell growth; tumorigenicity; cancer stem cells.
Received: July 14, 2013 Accepted: July 25, 2013 Published: July 27, 2013
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.
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