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