Abstract
The majority of patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein over-expression die of the disease. Here our analyses of RNA sequencing data identify the long noncoding RNA lncNB1 as one of the transcripts most over-expressed in MYCN-amplified, compared with MYCN-non-amplified, human neuroblastoma cells and also the most over-expressed in neuroblastoma compared with all other cancers. lncNB1 binds to the ribosomal protein RPL35 to enhance E2F1 protein synthesis, leading to DEPDC1B gene transcription. The GTPase-activating protein DEPDC1B induces ERK protein phosphorylation and N-Myc protein stabilization. Importantly, lncNB1 knockdown abolishes neuroblastoma cell clonogenic capacity in vitro and leads to neuroblastoma tumor regression in mice, while high levels of lncNB1 and RPL35 in human neuroblastoma tissues predict poor patient prognosis. This study therefore identifies lncNB1 and its binding protein RPL35 as key factors for promoting E2F1 protein synthesis, N-Myc protein stability and N-Myc-driven oncogenesis, and as therapeutic targets.
Highlights
The majority of patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein over-expression die of the disease
Bioinformatics analysis showed that a long noncoding RNAs (lncRNAs), which we named lncNB1, was one of the most overexpressed transcripts in MYCNamplified neuroblastoma cell lines. lncNB1 binds to the ribosomal protein ribosomal protein L35 (RPL35), leading to synthesis of E2F1 protein which induces DEPDC1B gene transcription
The lncRNA RP1-40E16.9 at chromosome 6: 3182817–3195767, known as LOC100507194 and LINC02525 but will be referred to as lncNB1, was polyadenylated and displayed an expression pattern very similar to N-Myc and MYCNOS (Fig. 1a, b), suggesting that this lncRNA could be involved in MYCN-amplified neuroblastoma tumorigenesis
Summary
The majority of patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein over-expression die of the disease. LncNB1 binds to the ribosomal protein RPL35 to enhance E2F1 protein synthesis, leading to DEPDC1B gene transcription. This study identifies lncNB1 and its binding protein RPL35 as key factors for promoting E2F1 protein synthesis, N-Myc protein stability and N-Myc-driven oncogenesis, and as therapeutic targets. Amplification of the MYCN oncogene and consequent over-expression of the N-Myc oncoprotein occur in approximately 25% of human neuroblastoma tissues and correlate with poor patient prognosis[1,2]. LncNB1 binds to the ribosomal protein RPL35, leading to synthesis of E2F1 protein which induces DEPDC1B gene transcription. The study identifies lncNB1, its binding protein RPL35 and their target DEPDC1B as key factors in N-Myc-driven oncogenesis and as therapeutic targets
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