The Long Noncoding RNA NBAT-1 Suppresses Neuroblastoma Progression

Neuroblastoma can be stratified into low- and high-risk subtypes based on factors such as patient age, disease stage, and nonrandom alterations in specific chromosomal regions. To identify additional biomarkers of neuroblastoma risk, Pandey, Mitra, and colleagues performed transcriptomic profiling to characterize the expression profiles of long noncoding RNAs (lncRNA) among low- and high-risk neuroblastomas. This analysis identified 24 nonannotated lncRNAs that were differentially expressed between the low- and high-risk subtypes, as well as lncRNAs that map to genomic regions that are commonly amplified or deleted in high-risk aggressive neuroblastoma, suggesting that lncRNAs may contribute to neuroblastoma progression. In particular, decreased expression of the lncRNA neuroblastoma-associated transcript-1 (NBAT-1, also known as CASC14) was detected in high-risk neuroblastoma compared with low-risk tumors and was associated with reduced probability of survival. The differential expression of NBAT-1 between neuroblastoma subtypes was mediated by hypermethylation of the NBAT-1 promoter in high-risk patients and the presence of a high-risk neuroblastoma–associated SNP within the NBAT-1 locus. Consistent with a role for NBAT-1 in suppressing neuroblastoma progression, depletion of NBAT-1 resulted in increased neuroblastoma cell proliferation and invasion both in vitro and in xenograft tumors. This tumor-suppressive function of NBAT-1 was dependent on epigenetic silencing of protumorigenic genes, including SOX9, OSMR, and VCAN, via interaction of NBAT-1 with the Polycomb repressive complex 2 component enhancer of zeste homolog 2 (EZH2). Furthermore, loss of NBAT-1 decreased the expression of neuronal lineage–specific genes and impaired neuronal differentiation of neuroblastoma cells via activation of RE1-silencing transcription factor (REST, also known as NRSF), which represses the expression of neuronal genes and was upregulated in high-risk neuroblastoma tumors characterized by impaired differentiation. Together, these results highlight NBAT-1 as a prognostic biomarker of clinical outcome and potential therapeutic target in neuroblastoma.

Pandey GK, Mitra S, Subhash S, Hertwig F, Kanduri M, Mishra K, et al. The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation. Cancer Cell 2014;26:722–37.