title: The long non-coding RNA GAS5 differentially regulates cell cycle arrest and apoptosis through activation of BRCA1 and p53 in human neuroblastoma.
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.
authors.affiliation: Department of Research, Nemours Children's Hospital, Orlando, FL 32827, USA.|Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Mazar
authors.affiliation: Department of Research, Nemours Children's Hospital, Orlando, FL 32827, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Rosado
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
authors.forename: John
authors.initials: J
authors.lastname: Shelley
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
authors.forename: John
authors.initials: J
authors.lastname: Marchica
authors.affiliation: Department of Research, Nemours Children's Hospital, Orlando, FL 32827, USA.
authors.forename: Tamarah J
authors.initials: TJ
authors.lastname: Westmoreland
mesh_terms: D017398:Alternative Splicing; D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D062085:RNA, Long Noncoding; D016159:Tumor Suppressor Protein p53; C492913:BRCA1 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C561567:GAS5 long non-coding RNA, human; C459801:MYCN protein, human; C495901:TP53 protein, human; C497206:MDM2 protein, human
keywords: GAS5; cancer; long non-coding RNA; neuroblastoma; p53