4804

NGFR

CD271|Gp80-LNGFR|TNFRSF16|p75(NTR)|p75NTR;nerve growth factor receptor;NGFR;nerve growth factor receptor

NGF receptor|TNFR superfamily, member 16|low affinity nerve growth factor receptor|low affinity neurotrophin receptor p75NTR|low-affinity nerve growth factor receptor|p75 ICD|tumor necrosis factor receptor superfamily member 16

17q21-q22

protein-coding

Neuroblastoma is the most common extracranial solid tumor of childhood. One important factor that predicts a favorable prognosis is the robust expression ofthe TRKA and p75NTR neurotrophin receptor genes. Interestingly, TRKA and p75NTR expression is often attenuated in aggressive MYCN-amplified tumors, suggesting acausal link between elevated MYCN activity and the transcriptional repression ofTRKA and p75NTR, but the precise mechanisms involved are unclear. Here, we show that MYCN acts directly to repress TRKA and p75NTR gene transcription. Specifically, we found that MYCN levels were critical for repression and that MYCN targeted proximal/core promoter regions by forming a repression complex with transcription factors SP1 and MIZ1. When bound to the TRKA and p75NTR promoters,MYCN recruited the histone deacetylase HDAC1 to induce a repressed chromatin state. Forced re-expression of endogenous TRKA and p75NTR with exposure to the HDAC inhibitor TSA sensitized neuroblastoma cells to NGF-mediated apoptosis. By directly connecting MYCN to the repression of TRKA and p75NTR, our findings establish a key pathway of clinical pathogenicity and aggressiveness in neuroblastoma.#CI- (c) 2010 AACR.

Neuroblastoma (NB) is the most common extracranial pediatric solid tumor with anundifferentiated status and generally poor prognosis, but the basis for these characteristics remains unknown. In this study, we show that upregulation of thePolycomb protein histone methyltransferase EZH2, which limits differentiation inmany tissues, is critical to maintain the undifferentiated state and poor prognostic status of NB by epigenetic repression of multiple tumor suppressor genes. We identified this role for EZH2 by examining the regulation of CASZ1, a recently identified NB tumor suppressor gene whose ectopic restoration inhibits NB cell growth and induces differentiation. Reducing EZH2 expression by RNA interference-mediated knockdown or pharmacologic inhibiton with 3-deazaneplanocin A increased CASZ1 expression, inhibited NB cell growth, and induced neurite extension. Similarly, EZH2(-/-) mouse embryonic fibroblasts (MEF) displayed 3-fold higher levels of CASZ1 mRNA compared with EZH2(+/+) MEFs. In cells with increased expression of CASZ1, treatment with histone deacetylase (HDAC) inhibitor decreased expression of EZH2 and the Polycomb Repressor complex component SUZ12. Under steady-state conditions, H3K27me3 and PRC2 components bound to the CASZ1 gene were enriched, but this enrichment was decreased after HDAC inhibitor treatment. We determined that the tumor suppressors CLU, NGFR, and RUNX3 were also directly repressed by EZH2 like CASZ1 in NB cells. Together, ourfindings establish that aberrant upregulation of EZH2 in NB cells silences several tumor suppressors, which contribute to the genesis and maintenance of the undifferentiated phenotype of NB tumors.#CI- (c)2011 AACR.

Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor.Major research efforts have focused on characterizing and targeting putative brain tumor stem or propagating cell populations from the tumor mass. However, less is known about the relationship between these cells and highly invasive MB cells that evade current therapies. Here, we dissected MB cellular heterogeneityand directly compared invasion and self-renewal. Analysis of higher versus lowerself-renewing tumor spheres and stationary versus migrating adherent MB cells revealed differential expression of the cell surface markers CD271 [p75 neurotrophin receptor (p75NTR)] and CD133. Cell sorting demonstrated that CD271 selects for subpopulations with a higher capacity for self-renewal, whereas CD133 selects for cells exhibiting increased invasion in vitro. CD271 expression is higher in human fetal cerebellum and primary samples of the Shh MB molecular variant and lower in the more aggressive, invasive group 3 and 4 subgroups. Global gene expression analysis of higher versus lower self-renewing MB tumor spheres revealed down-regulation of a cell movement transcription program in thehigher self-renewing state and a novel potential role for axon guidance signaling in MB-propagating cells. We have identified a cell surface signature based on CD133/CD271 expression that selects for MB cells with a higher self-renewal potential or invasive capacity in vitro. Our study underscores a previously unappreciated role for CD271 in selecting for MB cell phenotypes and suggests that successful treatment of pediatric brain tumors requires concomitant targeting of a spectrum of transitioning self-renewing and highly infiltrative cell subpopulations.