ArticlePLoS genetics2014
NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that inhibits GSK3β resulting in the stabilization of MYCN in human neuroblastomas.
Article in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 101 citations in OpenAlex.
- Mapping the functional dark proteome in cancer.Nature reviews. Cancer · 2026Review
- O-GlcNAcylation expression predicts a favorable prognosis and mitigates malignant phenotypes via MYCN suppression in neuroblastoma.Molecular and cellular pediatrics · 2026Article
- Article
- CCA-1.1 Destabilizes MYC proteins to induce irreversible anti-proliferative effects in hepatocellular carcinoma.Medical oncology (Northwood, London, England) · 2025Article
- De Novo Genes: Current Status and Future Goals.Genome biology and evolution · 2025Article
- Oncogenic roles of young human de novo genes and their potential as neoantigens in cancer immunotherapy.Cell genomics · 2025Article
- Subcellular Enrichment Patterns of New Genes in Drosophila Evolution.Molecular biology and evolution · 2025Article
- Super-enhancer MYCNOS-SE promotes chemoresistance in small cell lung cancer by recruiting transcription factors CTCF and KLF15.Oncogene · 2025Article
- NCYM facilitates cell proliferation and invasion in Wilms tumor by regulating SIX1/β-catenin axis.American journal of clinical and experimental urology · 2025Article
- De Novo Genes.Annual review of genetics · 2024Review
- Rp3: Ribosome profiling-assisted proteogenomics improves coverage and confidence during microprotein discovery.Nature communications · 2024Article
- High Polymorphism Levels of De Novo ORFs in a Yoruba Human Population.Genome biology and evolution · 2024Article
- The Rapid Evolution of De Novo Proteins in Structure and Complex.Genome biology and evolution · 2024Article
- A Synergistic, Cultivator Model of De Novo Gene Origination.Genome biology and evolution · 2024Article
- Inhibition of OCT4 binding at theFrontiers in oncology · 2024Article
- Towards understanding paleoclimate impacts on primate de novo genes.G3 (Bethesda, Md.) · 2023Article
- Evolution and implications of de novo genes in humans.Nature ecology & evolution · 2023Review
- DNA Ligase 4 Contributes to Cell Proliferation against DNA-PK Inhibition inInternational journal of molecular sciences · 2023Article
- Evolutionary origins and interactomes of human, young microproteins and small peptides translated from short open reading frames.Molecular cell · 2023Article
- Structural characterization of humanFrontiers in oncology · 2023Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The rearrangement of pre-existing genes has long been thought of as the major mode of new gene generation. Recently, de novo gene birth from non-genic DNA was found to be an alternative mechanism to generate novel protein-coding genes. However, its functional role in human disease remains largely unknown. Here we show that NCYM, a cis-antisense gene of the MYCN oncogene, initially thought to be a large non-coding RNA, encodes a de novo evolved protein regulating the pathogenesis of human cancers, particularly neuroblastoma. The NCYM gene is evolutionally conserved only in the taxonomic group containing humans and chimpanzees. In primary human neuroblastomas, NCYM is 100% co-amplified and co-expressed with MYCN, and NCYM mRNA expression is associated with poor clinical outcome. MYCN directly transactivates both NCYM and MYCN mRNA, whereas NCYM stabilizes MYCN protein by inhibiting the activity of GSK3β, a kinase that promotes MYCN degradation. In contrast to MYCN transgenic mice, neuroblastomas in MYCN/NCYM double transgenic mice were frequently accompanied by distant metastases, behavior reminiscent of human neuroblastomas with MYCN amplification. The NCYM protein also interacts with GSK3β, thereby stabilizing the MYCN protein in the tumors of the MYCN/NCYM double transgenic mice. Thus, these results suggest that GSK3β inhibition by NCYM stabilizes the MYCN protein both in vitro and in vivo. Furthermore, the survival of MYCN transgenic mice bearing neuroblastoma was improved by treatment with NVP-BEZ235, a dual PI3K/mTOR inhibitor shown to destabilize MYCN via GSK3β activation. In contrast, tumors caused in MYCN/NCYM double transgenic mice showed chemo-resistance to the drug. Collectively, our results show that NCYM is the first de novo evolved protein known to act as an oncopromoting factor in human cancer, and suggest that de novo evolved proteins may functionally characterize human disease.
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