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.

The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35

Milazzo, Giorgio;Ciaccio, Roberto;Perini, Giovanni;
2019

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.
Liu, Pei Y; Tee, Andrew E; Milazzo, Giorgio; Hannan, Katherine M; Maag, Jesper; Mondal, Sujanna; Atmadibrata, Bernard; Bartonicek, Nenad; Peng, Hui; Ho, Nicholas; Mayoh, Chelsea; Ciaccio, Roberto; Sun, Yuting; Henderson, Michelle J; Gao, Jixuan; Everaert, Celine; Hulme, Amy J; Wong, Matthew; Lan, Qing; Cheung, Belamy B; Shi, Leming; Wang, Jenny Y; Simon, Thorsten; Fischer, Matthias; Zhang, Xu D; Marshall, Glenn M; Norris, Murray D; Haber, Michelle; Vandesompele, Jo; Li, Jinyan; Mestdagh, Pieter; Hannan, Ross D; Dinger, Marcel E; Perini, Giovanni; Liu, Tao
File in questo prodotto:
File Dimensione Formato  
The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35.pdf

accesso aperto

Tipo: Versione (PDF) editoriale
Licenza: Licenza per Accesso Aperto. Creative Commons Attribuzione (CCBY)
Dimensione 2.53 MB
Formato Adobe PDF
2.53 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/705206
Citazioni
  • ???jsp.display-item.citation.pmc??? 31
  • Scopus 40
  • ???jsp.display-item.citation.isi??? 38
social impact