The stem cell-associated transcription co-factor ZNF521 has been implicated in the regulation of the homeostasis of the immature cell compartment in the hematopoietic, osteo-adipogenic and neural system. ZNF521 is highly expressed in cerebellum, particularly in the neonatal external granule layer that contains candidate cells-of-origin of medulloblastoma, and in the majority of human medullo- blastomas. 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 and primary Ptc1+/- mouse medulloblastoma cells was investigated in several types of in vitro and in vivo assays, by inducing enforced expression with lentiviral vectors carrying the ZNF521 cDNA, or by silencing its expression using distinct, specific shRNAs.
 Enforced overexpression of ZNF521 in DAOY medulloblastoma cells significantly increased their proliferation, growth as spheroids and clonogenicity in single-cell cultures and semisolid media, and strongly enhanced their migratory ability in wound-healing assays. Importantly, ZNF521-expressing cells exhibited a greatly augmented tumorigenic potential in nude mice. All these activities of ZNF521 required the integrity of its 12-AA-long N-terminal motif that recruits the nucleosome remodeling and histone deacetylase (NuRD) complex; this might therefore represent an appealing therapeutic target. Conversely, silencing of ZNF521 in UW228 medulloblastoma cells that display high baseline expression of its mRNA, decreased their proliferation, clonogenicity, sphere formation and wound-healing ability. Similarly, silencing of Zfp521 in mouse Ptc1+/- medulloblastoma cells drastically reduced their growth and tumorigenic potential. Taken together, our data strongly support the notion that ZNF521, through the recruitment of the NuRD complex, contributes to the clonogenic growth, migration and tumorigenicity of human and murine medulloblastoma cells.

Critical role of zinc finger protein 521 in the regulation of growth and tumourigenic potential of human medulloblastoma cells

Scicchitano S;Chiarella E;Mesuraca M;Bond HM;
2014-01-01

Abstract

The stem cell-associated transcription co-factor ZNF521 has been implicated in the regulation of the homeostasis of the immature cell compartment in the hematopoietic, osteo-adipogenic and neural system. ZNF521 is highly expressed in cerebellum, particularly in the neonatal external granule layer that contains candidate cells-of-origin of medulloblastoma, and in the majority of human medullo- blastomas. 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 and primary Ptc1+/- mouse medulloblastoma cells was investigated in several types of in vitro and in vivo assays, by inducing enforced expression with lentiviral vectors carrying the ZNF521 cDNA, or by silencing its expression using distinct, specific shRNAs.
 Enforced overexpression of ZNF521 in DAOY medulloblastoma cells significantly increased their proliferation, growth as spheroids and clonogenicity in single-cell cultures and semisolid media, and strongly enhanced their migratory ability in wound-healing assays. Importantly, ZNF521-expressing cells exhibited a greatly augmented tumorigenic potential in nude mice. All these activities of ZNF521 required the integrity of its 12-AA-long N-terminal motif that recruits the nucleosome remodeling and histone deacetylase (NuRD) complex; this might therefore represent an appealing therapeutic target. Conversely, silencing of ZNF521 in UW228 medulloblastoma cells that display high baseline expression of its mRNA, decreased their proliferation, clonogenicity, sphere formation and wound-healing ability. Similarly, silencing of Zfp521 in mouse Ptc1+/- medulloblastoma cells drastically reduced their growth and tumorigenic potential. Taken together, our data strongly support the notion that ZNF521, through the recruitment of the NuRD complex, contributes to the clonogenic growth, migration and tumorigenicity of human and murine medulloblastoma cells.
2014
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12317/23140
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