Risk-Associated Long Noncoding RNA FOXD3-AS1 Inhibits Neuroblastoma Progression by Repressing PARP1-Mediated Activation of CTCF.

Abstract

Neuroblastoma (NB) is the most common extracranial tumor in childhood. Recent studies have implicated the emerging roles of long noncoding RNAs (lncRNAs) in tumorigenesis and aggressiveness. However, the functions and targets of risk-associated lncRNAs in NB progression still remain to be determined. Herein, through mining of public microarray datasets, we identify lncRNA forkhead box D3 antisense RNA 1 (FOXD3-AS1) as an independent prognostic marker for favorable outcome of NB patients. FOXD3-AS1 is downregulated in NB tissues and cell lines, and ectopic expression of FOXD3-AS1 induces neuronal differentiation and decreases the aggressiveness of NB cells in vitro and in vivo. Mechanistically, as a nuclear lncRNA, FOXD3-AS1 interacts with poly(ADP-ribose) polymerase 1 (PARP1) to inhibit the poly(ADP-ribosyl)ation and activation of CCCTC-binding factor (CTCF), resulting in derepressed expression of downstream tumor-suppressive genes. Rescue experiments indicate that FOXD3-AS1 harbors tumor-suppressive properties by inhibiting the oncogenic roles of PARP1 or CTCF and plays crucial roles in all-trans-retinoic-acid-mediated therapeutic effects on NB. Administration of FOXD3-AS1 construct or siRNAs against PARP1 or CTCF reduces the tumor growth and prolongs the survival of nude mice. These findings suggest that as a risk-associated lncRNA, FOXD3-AS1 inhibits the progression of NB through repressing PARP1-mediated CTCF activation.

• Authors: Xiang Zhao, Dan Li, Dandan Huang, Huajie Song, Hong Mei, Erhu Fang, Xiaojing Wang, Feng Yang, Liduan Zheng, Kai Huang, Qiangsong Tong
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 26 Issue 3 Pg. 755-773 (03 07 2018) ISSN: 1525-0024 [Electronic] United States
• PMID: 29398485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)
• Copyright: Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers, Tumor
• CCCTC-Binding Factor
• FOXD3 protein, human
• Forkhead Transcription Factors
• RNA, Antisense
• RNA, Long Noncoding
• Tumor Suppressor Proteins
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1

Topics

• Animals
• Apoptosis (genetics)
• Biomarkers, Tumor
• CCCTC-Binding Factor (metabolism)
• Cell Line, Tumor
• Cell Survival
• Cell Transformation, Neoplastic (genetics, metabolism)
• Disease Models, Animal
• Disease Progression
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Neuroblastoma (genetics, metabolism, mortality, pathology)
• Poly (ADP-Ribose) Polymerase-1 (genetics, metabolism)
• Prognosis
• Protein Binding
• RNA Interference
• RNA, Antisense
• RNA, Long Noncoding
• Tumor Suppressor Proteins (genetics, metabolism)