Golgi-localized Ring Finger Protein 121 is necessary for MYCN-driven neuroblastoma tumorigenesis
MYCN amplification predicts poor prognosis in childhood neuroblastoma. To identify MYCN oncogenic signal dependencies we performed N-ethyl-N-nitrosourea (ENU) mutagenesis on the germline of neuroblastoma-prone TH-MYCN transgenic mice to generate founders which had lost tumorigenesis. Sequencing of the mutant mouse genomes identified the Ring Finger Protein 121 (RNF121<sup>WT</sup>) gene mutated to RNF<sup>M158R</sup> associated with heritable loss of tumorigenicity. While the RNF121<sup>WT</sup> protein localised predominantly to the cis-Golgi Complex, the RNF121<sup>M158R</sup> mutation in Helix 4 of its transmembrane domain caused reduced RNF121 protein stability and absent Golgi localisation. RNF121<sup>WT</sup> expression markedly increased during TH-MYCN tumorigenesis, whereas hemizygous RNF121<sup>WT</sup> gene deletion reduced TH-MYCN tumorigenicity. The RNF121<sup>WT</sup>-enhanced growth of MYCN-amplified neuroblastoma cells depended on RNF121<sup>WT</sup> transmembrane Helix 5. RNF121<sup>WT</sup> directly bound MYCN protein and enhanced its stability. High RNF121 mRNA expression associated with poor prognosis in human neuroblastoma tissues and another MYC-driven malignancy, laryngeal cancer. RNF121 is thus an essential oncogenic cofactor for MYCN and a target for drug development.
Authors
- Douglas J. Hilton (ORCID: https://orcid.org/0000-0002-7698-2392)
- Michael W. Parker (ORCID: https://orcid.org/0000-0002-3101-1138)
- Alice Salib (ORCID: https://orcid.org/0000-0003-4605-6432)
- Richard Young (ORCID: https://orcid.org/0000-0002-1409-4584)
- Murray D. Norris (ORCID: https://orcid.org/0000-0002-0632-4589)
- Belamy B. Cheung (ORCID: https://orcid.org/0000-0001-8784-860X)
- Benjamin T. Kile (ORCID: https://orcid.org/0000-0002-8836-8947)
- Mukesh Raipuria (ORCID: https://orcid.org/0000-0003-1662-0100)
- Lin Luo (ORCID: https://orcid.org/0000-0001-5556-7096)
- Ritu Mittra
- Benjamin Solomon (ORCID: https://orcid.org/0000-0003-3059-5730)
- Andrew J. Kueh (ORCID: https://orcid.org/0009-0005-9596-1422)
- Jennifer L. Stow (ORCID: https://orcid.org/0000-0002-5409-9101)
- Chelsea Mayoh (ORCID: https://orcid.org/0000-0002-6398-3046)
- Andrew J. Gifford (ORCID: https://orcid.org/0000-0002-4092-2347)
- Janith A. Seneviratne (ORCID: https://orcid.org/0000-0003-0413-5829)
- Shizhen Zhu (ORCID: https://orcid.org/0000-0002-2929-3279)
- Joanna Tsang
- David F. Restuccia (ORCID: https://orcid.org/0000-0001-7131-8065)
- Parisa Vahidi Ferdowsi (ORCID: https://orcid.org/0000-0002-6698-2823)
- Stéphane Chappaz (ORCID: https://orcid.org/0000-0003-0574-7544)
- Michelle Haber (ORCID: https://orcid.org/0000-0003-2036-8817)
- Darren L. Brown (ORCID: https://orcid.org/0000-0003-2174-7691)
- Iris Poh Ling Wong
- Selina K. Sutton
- Glenn M. Marshall (ORCID: https://orcid.org/0000-0002-2503-0762)
- Marco J. Herold (ORCID: https://orcid.org/0000-0001-7539-7581)
- Libby Huang (ORCID: https://orcid.org/0000-0001-7398-0570)
- Eric Sekyere
- Daniel R. Carter
- Jayne Murray (ORCID: https://orcid.org/0000-0002-1861-6570)
- Tao Liu (ORCID: https://orcid.org/0000-0001-6244-7316)
- Qian Wang (ORCID: https://orcid.org/0000-0002-6514-3470)
Institutions
- University of Technology Sydney (AU)
- Mayo Clinic (US)
- The University of Queensland (AU)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Peter MacCallum Cancer Centre (AU)
- Cancer Institute of New South Wales (AU)
- UNSW Sydney (AU)
- Children's Cancer Institute Australia (AU)
- St Vincent's Clinic (AU)
- Sydney Children's Hospital (AU)
- Monash University (AU)
- The University of Adelaide (AU)
- St Vincents Institute of Medical Research (AU)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-10-14
- DOI
- https://doi.org/10.1038/s42003-024-06899-8
- Citations
- 1
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.37
Funders
- Australian Government
- Cancer Institute NSW
- University of New South Wales
- University of Technology Sydney
- Monash University
- University of Melbourne
- University of Adelaide
- Peter MacCallum Cancer Centre
- Faculty of Health and Medical Sciences, University of Western Australia
- Center for Individualized Medicine, Mayo Clinic
- Medical Research Council
- National Health and Medical Research Council
- Cancer Council NSW
- Institute for Molecular Bioscience, University Of Queensland
- National Cancer Institute