Abstract LB-149: LYAR promotes cell proliferation by repressing CHAC1 expression in neuroblastoma

Abstract

Abstract Introduction: Neuroblastoma is a cancer of the sympathetic nervous system occurring mostly in infants and young children. Despite considerable progress in the treatment of neuroblastoma, 5-year survival rates have remained less than 50% for the majority of children with high-risk disease. Amplification of the MYCN oncogene and consequent overexpression of the N-Myc oncoprotein is a major prognostic indicator in neuroblastoma, which is strongly associated with aggressive tumour behaviour and poor patient outcome. N-Myc oncoprotein induces neuroblastoma by modulating gene and protein expression and consequently causing cell proliferation. LYAR (Ly-1 antibody reactive clone), a novel nucleolar protein with zinc finger DNA-binding motifs, is mostly involved in cell growth regulation in many cancers. Results: Here we showed that N-Myc up-regulated LYAR expression in neuroblastoma cells. Conversely, LYAR up-regulated N-Myc expression. Affymetrix gene array studies revealed that the gene most significantly repressed by LYAR siRNAs was ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1). Consistent with this finding, RT-PCR and immunoblot confirmed that LYAR siRNAs increased CHAC1 gene and protein expression. Alamar blue assays and cell cycle analyses demonstrated that LYAR induced MYCN-amplified neuroblastoma cell proliferation in a CHAC1-depedent manner. Additionally, high levels of LYAR gene expression in human neuroblastoma tissues were associated with MYCN gene expression and predicted poor patient survival independent of patient age and disease stage. Conclusions: Our data demonstrate LYAR as a potential target in neuroblastoma oncogenesis, and provide critical evidence to support the application of LYAR inhibitors for the therapy of neuroblastoma patients. Citation Format: Yuting Sun, Bernard Atmadibrata, Bing Liu, Tao Liu. LYAR promotes cell proliferation by repressing CHAC1 expression in neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-149.