Golgi-localized Ring Finger Protein 121 is necessary for MYCN-driven neuroblastoma tumorigenesis

Belamy B Cheung; Ritu Mittra; Jayne Murray; Qian Wang; Janith A Seneviratne; Mukesh Raipuria; Iris Poh Ling Wong; David Restuccia; Andrew Gifford; Alice Salib; Selina Sutton; Libby Huang; Parisa Vahidi Ferdowsi; Joanna Tsang; Eric Sekyere; Chelsea Mayoh; Lin Luo; Darren L Brown; Jennifer L Stow; Shizhen Zhu; Richard J Young; Benjamin J Solomon; Stephane Chappaz; Benjamin Kile; Andrew Kueh; Marco J Herold; Douglas J Hilton; Tao Liu; Murray D Norris; Michelle Haber; Daniel R Carter; Michael W Parker; Glenn M Marshall

doi:10.1038/s42003-024-06899-8

Golgi-localized Ring Finger Protein 121 is necessary for MYCN-driven neuroblastoma tumorigenesis

Commun Biol. 2024 Oct 14;7(1):1322. doi: 10.1038/s42003-024-06899-8.

Authors

Belamy B Cheung^#^{1

2}, Ritu Mittra^#³, Jayne Murray³, Qian Wang³, Janith A Seneviratne³, Mukesh Raipuria³, Iris Poh Ling Wong³, David Restuccia³, Andrew Gifford³, Alice Salib³, Selina Sutton³, Libby Huang³, Parisa Vahidi Ferdowsi³, Joanna Tsang³, Eric Sekyere³, Chelsea Mayoh^{3

4}, Lin Luo⁵, Darren L Brown⁵, Jennifer L Stow⁵, Shizhen Zhu⁶, Richard J Young⁷, Benjamin J Solomon⁷, Stephane Chappaz⁸, Benjamin Kile⁹, Andrew Kueh^{10

11}, Marco J Herold^{10

11}, Douglas J Hilton^{10

11}, Tao Liu^{3

12}, Murray D Norris^{3

12}, Michelle Haber^{3

4}, Daniel R Carter^{3

13}, Michael W Parker^{14

15}, Glenn M Marshall^{16

17}

Affiliations

¹ Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Sydney, Australia. [email protected].
² School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia. [email protected].
³ Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Sydney, Australia.
⁴ School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
⁵ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
⁶ Department of Biochemistry and Molecular Biology, Cancer Center and Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
⁷ Peter MacCallum Cancer Centre, Melbourne, Australia.
⁸ Anatomy & Developmental Biology, Monash University, Melbourne, Australia.
⁹ Faculty of Health and Medical Sciences at the University of Adelaide, Adelaide, Australia.
¹⁰ Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute, Melbourne, Australia.
¹¹ Department of Medical Biology, The University of Melbourne, Victoria, 3052, Australia.
¹² University of New South Wales Centre for Childhood Cancer Research, Sydney, NSW 2052, Australia.
¹³ School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia.
¹⁴ ACRF Facility for Innovative Cancer Drug Discovery and Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
¹⁵ ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
¹⁶ Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Sydney, Australia. [email protected].
¹⁷ Kids Cancer Centre, Sydney Children's Hospital, Sydney, 2031, NSW, Australia. [email protected].

^# Contributed equally.

Abstract

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^WT) gene mutated to RNF^M158R associated with heritable loss of tumorigenicity. While the RNF121^WT protein localised predominantly to the cis-Golgi Complex, the RNF121^M158R mutation in Helix 4 of its transmembrane domain caused reduced RNF121 protein stability and absent Golgi localisation. RNF121^WT expression markedly increased during TH-MYCN tumorigenesis, whereas hemizygous RNF121^WT gene deletion reduced TH-MYCN tumorigenicity. The RNF121^WT-enhanced growth of MYCN-amplified neuroblastoma cells depended on RNF121^WT transmembrane Helix 5. RNF121^WT 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.

MeSH terms

Animals
Carcinogenesis / genetics
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Golgi Apparatus / metabolism
Humans
Mice
Mice, Transgenic
N-Myc Proto-Oncogene Protein* / genetics
N-Myc Proto-Oncogene Protein* / metabolism
Neuroblastoma* / genetics
Neuroblastoma* / metabolism
Neuroblastoma* / pathology

Substances

N-Myc Proto-Oncogene Protein
MYCN protein, human

Abstract

MeSH terms

Substances

Grants and funding