Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors.

Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.

These data suggest that the cleavage of FLNA by calpain is an important cellular event in the regulation of tumor cell growth.

eThe phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110␣ is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110␣. Very little is known about the metabolic consequences of the hot spot mutations of p110␣ in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110␣ expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110␣ mutants was surprisingly not dependent on altered p110␣ lipid kinase activity. Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of several signaling pathways, including insulin-like growth factor 1 (IGF-1) and insulin signaling (1). Upon activation by IGF-1, insulin, or other growth factors, it catalyzes the formation of phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), which has a high affinity for the pleckstrin homology (PH) domain of the downstream target Akt/protein kinase B (Akt/ PKB). The interaction of PIP 3 with the PH domain enables phosphorylation of Akt/PKB by phosphoinositide-dependent kinase 1 (PDK 1) and PDK 2. PI3K and Akt/PKB are both critical nodes in many intracellular signaling pathways and are imperative for the actions of IGF-1, insulin, and other growth factors (2).Class IA PI3Ks consist of two subunits. The catalytic subunit, p110, contains the kinase domain responsible for the formation of PIP 3 . The regulatory subunit, usually designated p85, binds to phosphorylated tyrosine residues in other proteins via its SH2 domain, leading to subsequent activation of the kinase. Both subunits exist as several different isoforms. There are four known human catalytic subunit isoforms: p110␣, p110␤, p110␦, and p37␦. p110␣, p110␤, and p110␦ are encoded by three different genes, i.e., PIK3CA, PIK3CB, and PIK3CD, respectively (reviewed in reference 1), whereas p37␦ (PIK3CD_v2) is a splice variant of p110␦ (3). We and others have shown that among the catalytic subunits, p110␣ is the major contributor to transmission of the insulin signal (4-6), whereas p110␤ becomes active primarily in response to G-protein-coupled receptor signaling and plays a role in proliferation (7,8). p110␦ is more cell specific than p110␣ and p110␤ and plays an important role in immune cells and the embryonic nervous system (9-11).p110␣ is the most frequently mutated kinase in human cancer; three mutations in particular, often referred to as the hot spot mutations, namely, E542K, E545K, and H1047R, are the most common in p110␣ (PIK3CA) and comprise 80% of all mutations (reviewed in ref...

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