ZNF238 is expressed in postmitotic brain cells and inhibits brain tumor growth.
Brain tumors such as medulloblastoma (MB) and glioblastoma multiforme (GBM) can derive from neural precursors. For instance, many MBs are thought to arise from the uncontrolled proliferation of cerebellar granule neuron precursors (GNP). GNPs normally proliferate in early postnatal stages in mice but then they become postmitotic and differentiate into granule neurons. The proliferation of neural precursors, GNPs, as well as at least subsets of GBM and MB depends on Hedgehog signaling. However, the gene functions that are lost or suppressed in brain tumors and that normally promote the proliferation arrest and differentiation of precursors remain unclear. Here we have identified a member of the BTB-POZ and zinc finger family, ZNF238, as a factor highly expressed in postmitotic GNPs and differentiated neurons. In contrast, proliferating GNPs as well as MB and GBM express low or no ZNF238. Functionally, inhibition of ZNF238 expression in mouse GNPs decreases the expression of the neuronal differentiation markers MAP2 and NeuN and downregulates the expression of the cell cycle arrest protein p27, a regulator of GNP differentiation. Conversely, reinstating ZNF238 expression in MB and GBM cells drastically decreases their proliferation and promotes cell death. It also downregulates cyclin D1 while increasing MAP2 and p27 protein levels. Importantly, ZNF238 antagonizes MB and GBM tumor growth in vivo in xenografts. We propose that the antiproliferative functions of ZNF238 in normal GNPs and possibly other neural precursors counteract brain tumor formation. ZNF238 is thus a novel brain tumor suppressor and its reactivation in tumors could open a novel anticancer strategy.
Tatard
Valérie M
VM
The Wistar Institute, Philadelphia, Pennsylvania, USA.
Xiang
Chaomei
C
Biegel
Jaclyn A
JA
Dahmane
Nadia
N
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008938:Mitosis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
C493961:Cdkn1b protein, mouse; D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D012097:Repressor Proteins; C115048:ZBTB18 protein, human; C520669:Zbtb18 protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27