Oncotarget

Research Papers:

The long non-coding RNA GAS5 differentially regulates cell cycle arrest and apoptosis through activation of BRCA1 and p53 in human neuroblastoma

Joseph Mazar _, Amy Rosado, John Shelley, John Marchica and Tamarah J. Westmoreland

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Oncotarget. 2017; 8:6589-6607. https://doi.org/10.18632/oncotarget.14244

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Abstract

Joseph Mazar1,2, Amy Rosado1, John Shelley2, John Marchica2, Tamarah J. Westmoreland1

1Department of Research, Nemours Children’s Hospital, Orlando, FL 32827, USA

2Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA

Correspondence to:

Joseph Mazar, email: jm0151@nemours.org

Keywords: long non-coding RNA, neuroblastoma, cancer, GAS5, p53

Received: July 22, 2016     Accepted: November 30, 2016     Published: December 27, 2016

ABSTRACT

The long non-coding RNA GAS5 has been shown to modulate cancer proliferation in numerous human cancer systems and has been correlated with successful patient outcome. Our examination of GAS5 in neuroblastoma has revealed robust expression in both MYCN-amplified and non-amplified cell lines. Knockdown of GAS5 In vitro resulted in defects in cell proliferation, apoptosis, and induced cell cycle arrest. Further analysis of GAS5 clones revealed multiple novel splice variants, two of which inversely modulated with MYCN status. Complementation studies of the variants post-knockdown of GAS5 indicated alternate phenotypes, with one variant (FL) considerably enhancing cell proliferation by rescuing cell cycle arrest and the other (C2) driving apoptosis, suggesting a unique role for each in neuroblastoma cancer physiology. Global sequencing and ELISA arrays revealed that the loss of GAS5 induced p53, BRCA1, and GADD45A, which appeared to modulate cell cycle arrest in concert. Complementation with only the FL GAS5 clone could rescue cell cycle arrest, stabilizing HDM2, and leading to the loss of p53. Together, these data offer novel therapeutic targets in the form of lncRNA splice variants for separate challenges against cancer growth and cell death.


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