Did you ever wonder what RNA rings, so called circular RNAs have to do with neuroblastoma – Steffen Fuchs
Did you ever wonder what RNA rings, so called circular RNAs (circRNAs) have to do with the childhood cancer neuroblastoma? Actually, more than you might think. Check out our recent publication in Nature Comms (https://rdcu.be/df0jk). I’m excited to share it with you!
circRNAs are ring-shaped RNAs important for gene expression regulation, e.g. by interacting with proteins or other RNAs. They were shown to be dynamically expressed in neural tissues during differentiation. Here, we investigated the role of circRNAs in the pediatric cancer neuroblastoma (NB).
Besides the MYCN gene as an oncogenic driver which is amplified in 20% of cases, there are not many recurrent genomic aberrations known that fully explain the disease. Noncoding RNAs have been investigated in neuroblastoma, but research is primarily limited to miRNAs and lncRNAs.
We therefore wanted to know, whether circRNAs are involved in neuroblastoma formation by analyzing a cohort of 104 primary patient samples through total RNA-seq. We detected more than 5,000 circRNAs (after stringent filtering) and detected several circRNA hotspots.
circRNA expression was neuroblastoma risk-group specific and allowed clustering of samples. Interestingly, the high-risk neuroblastomas harboring a MYCN amplification showed the lowest expression of circRNAs. We showed that this was a direct MYCN effect.
RNA-binding proteins (RBPs) are known regulators of circRNA biogenesis. By clustering circRNAs and RBPs, we identified DHX9 as a negative regulator of circRNAs in NB. Aktas et al. showed already the same effect in HEK293T cells. We added that MYCN directly regulates DHX9 levels. This was as well the case in the pediatric brain tumor medulloblastoma (5-10% MYCN amp.).
Next, we compared our results with a mixed cancer dataset and healthy controls, and identified 26 circRNAs specifically upregulated in NB. Among those was a circRNA derived of the ARID1A gene. Knockdown of circARID1A induced cell death and inhibited proliferation of NB cells.
How did circARID1A do this? To solve this, we performed a pulldown and RIP assay and identified the KHSRP RBP as an interaction partner. circARID1A stabilized KHSRP to influence TP53 signaling.
This was a huge team effort: thank you all!
And a multi-institution effort of Charité – Universitätsmedizin Berlin Berlin Institute of Health in der Charité Max Delbrück Center DKTK and IUCT-Oncopole /CRCT.
Finally, I would like to thank the funders: Deutsche Forschungsgemeinschaft (DFG) – German Research Foundation Berlin Institute of Health in der Charité, DKTK, Eva pour la Vie, the supportive editors of Nature Comms, and the reviewers, who really helped to improve the paper!
For article: Click here