Poster Presentation 39th Annual Lorne Genome Conference 2018

Four gene regulatory functions of oncogenic potential for NONO protein in neuroblastoma (#131)

Jack A L Cooper 1 , Alina Naveed 1 , Ryan Lister 2 , Archa Fox 1 2
  1. School of Human Sciences, The University of Western Australia, Perth, WA, Australia
  2. School of Molecular Sciences, The University of Western Australia, Perth, WA, Australia

Neuroblastoma is a childhood cancer characterised by complex, heterogeneous genetics and gene regulation. The long-term survival rate of high risk neuroblastoma patients is less than 50%, due in large part to the lack of targeted treatment. Neuroblastomas show few recurrent genetic mutations. Instead, it has been suggested that the cancer is driven by aberrant activity of the numerous gene regulators which are active in the development of neural-derived tissue. One such gene regulator is NONO, a protein whose expression has been strongly associated with poor prognosis in neuroblastoma. However, no comprehensive mechanism has yet been offered to explain this connection. By integrating PAR-CLIP, ChIP and NONO knockdown RNA sequencing datasets, we have obtained evidence for four gene regulatory functions for NONO with connections to tumorigenesis. Firstly, NONO binds to pre-mRNA transcripts to decrease their abundance. Secondly, NONO directs alternate splicing, and appears to promote the formation of a truncated transcript of the ALK oncogene. Thirdly, NONO modulates the activity of the CREB1 transcription factor, whose dysregulation has previously been associated with multiple cancers. Fourthly, NONO indirectly upregulates the targets of cholesterogenic transcription factor SREBP1A, enhancing cholesterol synthesis – a biological process whose upregulation is prognostic for poor outcome in neuroblastoma. As the first study to comprehensively characterise NONO’s activity in neuroblastoma, we lay the foundations for targeted investigation of NONO’s potential as a therapeutic target. Future work will confirm the importance of each of NONO’s functions to its association with neuroblastoma and other cancers.