Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN

Steffen Fuchs (), Clara Danßmann, Filippos Klironomos, Annika Winkler, Jörg Fallmann, Louisa-Marie Kruetzfeldt, Annabell Szymansky, Julian Naderi, Stephan H. Bernhart, Laura Grunewald, Konstantin Helmsauer, Elias Rodriguez-Fos, Marieluise Kirchner, Philipp Mertins, Kathy Astrahantseff, Christin Suenkel, Joern Toedling, Fabienne Meggetto, Marc Remke, Peter F. Stadler, Patrick Hundsdoerfer, Hedwig E. Deubzer, Annette Künkele, Peter Lang, Jörg Fuchs, Anton G. Henssen, Angelika Eggert, Nikolaus Rajewsky, Falk Hertwig and Johannes H. Schulte ()
Additional contact information
Steffen Fuchs: Charité - Universitätsmedizin Berlin
Clara Danßmann: Charité - Universitätsmedizin Berlin
Filippos Klironomos: Charité - Universitätsmedizin Berlin
Annika Winkler: Charité - Universitätsmedizin Berlin
Jörg Fallmann: University of Leipzig
Louisa-Marie Kruetzfeldt: Charité - Universitätsmedizin Berlin
Annabell Szymansky: Charité - Universitätsmedizin Berlin
Julian Naderi: Charité - Universitätsmedizin Berlin
Stephan H. Bernhart: University of Leipzig
Laura Grunewald: Charité - Universitätsmedizin Berlin
Konstantin Helmsauer: Experimental and Clinical Research Center (ECRC) of the Charité and Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
Elias Rodriguez-Fos: Charité - Universitätsmedizin Berlin
Marieluise Kirchner: Berlin Institute of Health at Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC)
Philipp Mertins: Berlin Institute of Health at Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC)
Kathy Astrahantseff: Charité - Universitätsmedizin Berlin
Christin Suenkel: Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
Joern Toedling: Charité - Universitätsmedizin Berlin
Fabienne Meggetto: Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse
Marc Remke: Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf
Peter F. Stadler: University of Leipzig
Patrick Hundsdoerfer: Helios Klinikum Berlin-Buch
Hedwig E. Deubzer: Charité - Universitätsmedizin Berlin
Annette Künkele: Charité - Universitätsmedizin Berlin
Peter Lang: University Children’s Hospital, Eberhard Karls University Tuebingen
Jörg Fuchs: University Children’s Hospital, Eberhard Karls University Tuebingen
Anton G. Henssen: Charité - Universitätsmedizin Berlin
Angelika Eggert: Charité - Universitätsmedizin Berlin
Nikolaus Rajewsky: Charité - Universitätsmedizin Berlin
Falk Hertwig: Charité - Universitätsmedizin Berlin
Johannes H. Schulte: Charité - Universitätsmedizin Berlin

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Circular RNAs (circRNAs) are a regulatory RNA class. While cancer-driving functions have been identified for single circRNAs, how they modulate gene expression in cancer is not well understood. We investigate circRNA expression in the pediatric malignancy, neuroblastoma, through deep whole-transcriptome sequencing in 104 primary neuroblastomas covering all risk groups. We demonstrate that MYCN amplification, which defines a subset of high-risk cases, causes globally suppressed circRNA biogenesis directly dependent on the DHX9 RNA helicase. We detect similar mechanisms in shaping circRNA expression in the pediatric cancer medulloblastoma implying a general MYCN effect. Comparisons to other cancers identify 25 circRNAs that are specifically upregulated in neuroblastoma, including circARID1A. Transcribed from the ARID1A tumor suppressor gene, circARID1A promotes cell growth and survival, mediated by direct interaction with the KHSRP RNA-binding protein. Our study highlights the importance of MYCN regulating circRNAs in cancer and identifies molecular mechanisms, which explain their contribution to neuroblastoma pathogenesis.

Date: 2023
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DOI: 10.1038/s41467-023-38747-4

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